Thyroid Hormones and Mitochondria abstracts · hormones: presence and action of steroid and thyroid...

References 4 website: JMR, http://fluoroquinolonethyroid.com

References 4

Links, Abstracts, Articles, etc.

These links should work as of 2014; sometimes you have to click on them

several times; if they don’t work, then Google/search the titles

Thyroid Hormones and Mitochondria abstracts The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells.

Authors

Psarra AM, Solakidi S, Sekeris CE

Source

Molecular and cellular endocrinology 246:1-2 2006 Feb 26 pg 21-33

Abstract

Mitochondria are key cellular organelles that regulate events related to energy production and apoptosis. These processes are modulated, in turn, by steroid and thyroid hormones in the course of their actions on metabolism, growth and development. In this context, a direct effect of these hormones on the mitochondrial-linked processes, possibly by way of cognate mitochondrial receptors, has been proposed. In this paper we review data from the literature and present new findings supporting this concept. Receptors for steroid hormones, glucocorticoids and estrogens, and for T(3), have been detected in mitochondria by immunofluorescence labeling and confocal laser microscopy, by Western blotting of mitochondrial proteins and by immunogold electron microscopy. Furthermore, the mitochondrial genome contains nucleotide sequences with high similarity to known hormone-responsive elements, which interact with the appropriate receptors to confer hormone-dependent activation of reporter genes in transfection experiments. Thus, thyroid hormone stimulates mitochondrial transcription mediated by the cognate receptor when added to an in organello mitochondrial system, capable of faithful transcription.

Mitochondrial genes as sites of primary action of steroid hormones.

Authors

Demonacos CV, Karayanni N, Hatzoglou E, Tsiriyiotis C, Spandidos DA, Sekeris CE

Source

Steroids 61:4 1996 Apr pg 226-32

http://www.unboundmedicine.com/medline/?st=M&author=Demonacos%20CVhttp://www.unboundmedicine.com/medline/?st=M&author=Karayanni%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Hatzoglou%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Tsiriyiotis%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Spandidos%20DAhttp://www.unboundmedicine.com/medline/?st=M&author=Sekeris%20CEhttp://www.unboundmedicine.com/medline/?st=M&journal=Steroids


Abstract

Steroid and thyroid hormones act on nuclear gene transcription by activating protein receptors, which in turn bind to hormone response elements (HREs). Among these cell-specific processes regulated by steroid receptors is energy metabolism through increased synthesis of respiratory enzymes. As some of these enzymes are encoded by both nuclear and mitochondrial genes, coordination of their synthesis is probable, inter alia at the transcriptional level. We have postulated a direct effect of steroid hormones on mitochondrial gene transcription and here present the following evidence in support of this hypothesis. 1) The human and rodent mitochondrial genomes contain nucleotide sequences similar both to type I and type II HREs. 2) Glucocorticoid receptors (GR) rapidly translocate from the cytoplasm into mitochondria after administration of glucocorticoids. This process has been reproduced in vitro and deletion of the N-terminal part of the glucocorticoid receptor stops translocation into mitochondria. 3) Gel shift analysis has demonstrated binding of GR to putative mitochondrial GR elements. 4) In transfection experiments, mitochondrial HREs confer dexamethasone inducibility on hybrid reporter constructs, abolished in the presence of excess RU38486. 5) Similar results were obtained for thyroid hormone receptor (TR alpha) localization, import, and binding to TR elements. These findings, taken with the demonstrated effects of steroid (and thyroid) hormones on mitochondrial transcription and respiratory enzyme biosynthesis, strongly support the hypothesis of a direct effect of steroid (and thyroid) hormones on mitochondrial gene transcription.

Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells.

Authors

Scheller K, Seibel P, Sekeris CE

Source

International review of cytology 222: 2003 pg 1-61

Abstract

This article concerns the localization of glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. The receptors are discussed in terms of their potential role in the regulation of mitochondrial transcription and energy production by the oxidative phosphorylation pathway, realized both by nuclear-encoded and mitochondrially encoded enzymes. A brief survey of the role of glucocorticoid and thyroid hormones on energy metabolism is presented, followed by a description of the molecular mode of action of these hormones and of the central role of the receptors in regulation of transcription. Subsequently, the structure and characteristics of glucocorticoid and thyroid hormone receptors are described, followed by a section on the effects of glucocorticoid and thyroid hormones on the transcription of mitochondrial and nuclear genes encoding subunits of OXPHOS and by an introduction to the mitochondrial genome and its transcription. A comprehensive description of the data demonstrates the localization of glucocorticoid and thyroid hormone receptors in mitochondria as well as the detection of potential hormone response elements that bind to these receptors. This leads to the conclusion that the receptors potentially play a role in the regulation of transcription of mitochondrial genes. The in organello mitochondrial system, which is capable of sustaining transcription in the absence of nuclear participation, is presented, responding to T3 with increased transcription rates, and the central role of a thyroid receptor isoform in the transcription effect is emphasized. Lastly, possible ways of coordinating nuclear and mitochondrial gene transcription in response to glucocorticoid and thyroid hormones are discussed, the hormones acting directly on the genes of the two compartments by way of common hormone response elements and indirectly on mitochondrial genes by stimulation of nuclear-encoded transcription factors.

http://www.unboundmedicine.com/medline/?st=M&author=Scheller%20Khttp://www.unboundmedicine.com/medline/?st=M&author=Seibel%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Sekeris%20CEhttp://www.unboundmedicine.com/medline/?st=M&journal=Int%20Rev%20Cytol


Thyroid hormone action in mitochondria.

Authors

Wrutniak-Cabello C, Casas F, Cabello G

Source

Journal of molecular endocrinology 26:1 2001 Feb pg 67-77

Abstract

Triiodothyronine (T3) is considered a major regulator of mitochondrial activity. In this review, we show evidence of the existence of a direct T3 mitochondrial pathway, and try to clarify the respective importance of the nuclear and mitochondrial pathways for organelle activity. Numerous studies have reported short-term and delayed T3 stimulation of mitochondrial oxygen consumption. Convincing data indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 mediators of this short-term influence, the detection of specific T3-binding sites, probably corresponding to a 28 kDa c-Erb Aalpha1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mechanisms elicited at the nuclear level, including changes in phospholipid turnover and stimulation of uncoupling protein expression, leading to an increased inner membrane proton leak. However, the involvement of a direct mitochondrial T3 pathway leading to a rapid stimulation of mitochondrial protein synthesis has to be considered. Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb Aalpha1 protein located in the mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a mitochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves both pathways. In particular, the c-erb Aalpha gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins. Recent studies concerning the physiological importance of the direct mitochondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation of cell differentiation. As the processes leading to or resulting from differentiation are energy-consuming, p43 coordination of metabolism and differentiation could be of significant importance in the regulation of development.

Regulation of mitochondrial biogenesis by thyroid hormone.

Authors

Weitzel JM, Iwen KA, Seitz HJ

Source

Experimental physiology 88:1 2003 Jan pg 121-8

Abstract

Thyroid hormone (T3) has a profound effect on mitochondrial biogenesis. T3-regulated gene expression is mediated by thyroid hormone receptor (TR) binding to thyroid hormone response elements (TREs). In concert with the action of various coactivators and corepressors this interaction leads to a modulation of the chromatin structure and subsequently to a modulation of gene expression of adjacent target genes.

http://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Mol%20Endocrinolhttp://www.unboundmedicine.com/medline/?st=M&author=Weitzel%20JMhttp://www.unboundmedicine.com/medline/?st=M&author=Iwen%20KAhttp://www.unboundmedicine.com/medline/?st=M&author=Seitz%20HJhttp://www.unboundmedicine.com/medline/?st=M&journal=Exp%20Physiol


However, as numerous genes are endogenously regulated by T3, and a TRE appears to be absent in their regulatory elements, a TR-independent pathway of T3-mediated gene regulation is likely. In this review, we discuss the direct mechanisms of TR-dependent regulation of gene expression on the nuclear and mitochondrial genome by T3. We also summarize recent observations on an indirect mechanism of T3 action via intermediate factor(s). We discuss the regulation of nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) by T3, suggesting NRF-1 and PGC-1alpha as attractive candidates for an intermediate factor of T3 action in vivo.

Triiodothyronine mitochondrial receptors: import and molecular mechanisms.

Authors

Wrutniak-Cabello C, Carazo A, Casas F, Cabello G

Source

Journal de la Société de biologie 202:2 2008 pg 83-92

Abstract

Thyroid hormone exerts a diversity of physiological influences over developmental and metabolic processes. Searching for receptors able to mediate this extended regulation led to the identification of triiodothyronine (T3) nuclear receptors encoded by two different genes, c-erbA alpha (TR alpha) and c-erbA beta (TR beta). More recently, two N-terminally truncated forms of the triiodothyronine nuclear receptor TR alpha 1, with molecular weights of 43 and 28 kDa, have been discovered in mitochondria. Synthesized through the use of internal initiation sites of translation occurring in the TR alpha 1 transcript, they are addressed into mitochondria according to an atypical process. Two mitochondrial import sequences have been characterized in the C-terminal part of these proteins; in addition, their N-terminal part, devoid of negative charges, plays a permissive role in this import. Whereas the function of p28 remains unknown, p43 is a T3-dependent transcription factor of the mitochondrial genome, acting through dimeric complexes involving at least two other truncated forms of nuclear receptors, mtRXR and mtPPAR. P43 activation by T3 stimulates mitochondrial protein synthesis, respiratory chain activity and mitochondriogenesis. Through the mitochondrial/nuclear crosstalk, this direct T3 mitochondrial pathway influences the expression of nuclear genes involved in the regulation of cell proliferation and differentiation. In particular, in myoblasts, p43 overexpression stimulates terminal differentiation and induces a preferential expression of slow myosin, by down-regulating c-Myc expression and up-regulating calcineurin and myogenin expression. Comparison of the respective influences of the nuclear and mitochondrial T3 pathways demonstrates either both additivity (myoblast differentiation), complementarity (mitochondriogenesis, myoblast differentiation) or opposite influences (myosin expression), thus indicating that these two pathways introduce a fine-tuning of the hormone influence.

Mitochondrial T3 receptor p43 regulates insulin secretion and glucose homeostasis.

Authors

Blanchet E, Bertrand C, Annicotte JS, Schlernitzauer A, Pessemesse L, Levin J, Fouret G, Feillet-Coudray C, Bonafos B, Fajas L, Cabello G, Wrutniak-Cabello C, Casas F

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26:1 2012 Jan pg 40-50

http://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Carazo%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Soc%20Biolhttp://www.unboundmedicine.com/medline/?st=M&author=Blanchet%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Bertrand%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Annicotte%20JShttp://www.unboundmedicine.com/medline/?st=M&author=Schlernitzauer%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Fouret%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Bonafos%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Fajas%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20J


Abstract

Thyroid hormone is a major determinant of energy expenditure and a key regulator of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine receptor (p43) that acts as a mitochondrial transcription factor of the organelle genome, which leads, in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Here we generated mice specifically lacking p43 to address its physiological influence. We found that p43 is required for normal glucose homeostasis. The p43(-/-) mice had a major defect in insulin secretion both in vivo and in isolated pancreatic islets and a loss of glucose-stimulated insulin secretion. Moreover, a high-fat/high-sucrose diet elicited more severe glucose intolerance than that recorded in normal animals. In addition, we observed in p43(-/-) mice both a decrease in pancreatic islet density and in the activity of complexes of the respiratory chain in isolated pancreatic islets. These dysfunctions were associated with a down-regulation of the expression of the glucose transporter Glut2 and of Kir6.2, a key component of the K(ATP) channel. Our findings establish that p43 is an important regulator of glucose homeostasis and pancreatic β-cell function and provide evidence for the first time of a physiological role for a mitochondrial endocrine receptor.

Mice lacking the p43 mitochondrial T3 receptor become glucose intolerant and insulin resistant during aging.

Authors

Bertrand C, Blanchet E, Pessemesse L, Annicotte JS, Feillet-Coudray C, Chabi B, Levin J, Fajas L, Cabello G, Wrutniak-Cabello C, Casas F

Source

PloS one 8:9 2013 pg e75111

Abstract

Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43-/- mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43-/- mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43-/- mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.

http://www.unboundmedicine.com/medline/?st=M&author=Bertrand%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Blanchet%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Annicotte%20JShttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Chabi%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Fajas%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=PLoS%20One


Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes.

Authors

Barbe P, Larrouy D, Boulanger C, Chevillotte E, Viguerie N, Thalamas C, Oliva Trastoy M, Roques M, Vidal H, Langin D

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15:1 2001 Jan pg 13-15

Abstract

Triiodothyronine (T3) increases mitochondrial respiration and promotes the uncoupling between oxygen consumption and ATP synthesis. T3 effect is mediated partly through transcriptional control of genes encoding mitochondrial proteins. We determined the effect of T3 on mRNA levels of uncoupling proteins (UCP) and proteins involved in the biogenesis of the respiratory chain in human skeletal muscle and on UCP2 mRNA expression in adipose tissue. Ten young, healthy males received 75 to 100 5g of T3 per day for 14 days. The increase in plasma-free T3 levels was associated with an increase of resting metabolic rate and a decrease of respiratory quotient. In skeletal muscle, treatment with T3 induced a twofold increase of both UCP2 and UCP3 mRNA levels (p c oxidase subunits 2 and 4, nuclear respiratory factor 1, mitochondrial transcription factor A, and the co-activator PGC1 did not change during the treatment. In adipose tissue, UCP2 mRNA levels increased threefold. The direct effect of T3 on skeletal muscle an d adipose tissue UCP2 and UCP3 mRNA expression was demonstrated in vitro in human primary cultures. Our data show that T3 induces UCP2 and UCP3 mRNA expression in humans. In skeletal muscle, UCP regulation by T3 is not associated with the transcriptional regulation of respiratory chain proteins.

Overexpression of the mitochondrial T3 receptor p43 induces a shift in skeletal muscle fiber types.

Authors

Casas F, Pessemesse L, Grandemange S, Seyer P, Gueguen N, Baris O, Lepourry L, Cabello G, Wrutniak-Cabello C

Source

PloS one 3:6 2008 pg e2501

Abstract

In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation. We have generated mice overexpressing p43 under control of the human alpha-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body

http://www.unboundmedicine.com/medline/?st=M&author=Barbe%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Larrouy%20Dhttp://www.unboundmedicine.com/medline/?st=M&author=Boulanger%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Chevillotte%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Viguerie%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Thalamas%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Oliva%20Trastoy%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Roques%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Vidal%20Hhttp://www.unboundmedicine.com/medline/?st=M&author=Langin%20Dhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Gueguen%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Baris%20Ohttp://www.unboundmedicine.com/medline/?st=M&author=Lepourry%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&journal=PLoS%20One


temperature 0.8 degrees C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1alpha and PPARdelta, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1alpha and PPARdelta.

Depletion of the p43 mitochondrial T3 receptor in mice affects skeletal muscle development and activity.

Authors

Pessemesse L, Schlernitzauer A, Sar C, Levin J, Grandemange S, Seyer P, Favier FB, Kaminski S, Cabello G, Wrutniak-Cabello C, Casas F

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26:2 2012 Feb pg 748-56

Abstract

In vertebrates, skeletal muscle myofibers display different contractile and metabolic properties associated with different mitochondrial content and activity. We have previously identified a mitochondrial triiodothyronine receptor (p43) regulating mitochondrial transcription and mitochondrial biogenesis. When overexpressed in skeletal muscle, it increases mitochondrial DNA content, stimulates mitochondrial respiration, and induces a shift in the metabolic and contractile features of muscle fibers toward a slower and more oxidative phenotype. Here we show that a p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity in skeletal muscle in association with the induction of a more glycolytic muscle phenotype and a decrease of capillary density. In addition, p43(-/-) mice displayed a significant increase in muscle mass relative to control animals and had an improved ability to use lipids. Our findings establish that the p43 mitochondrial receptor strongly affects muscle mass and the metabolic and contractile features of myofibers and provides evidence that this receptor mediates, in part, the influence of thyroid hormone in skeletal muscle.

Differential effects of thyroid hormones on energy metabolism of rat slow- and fast-twitch muscles.

Authors

Bahi L, Garnier A, Fortin D, Serrurier B, Veksler V, Bigard AX, Ventura-Clapier R

Source

Journal of cellular physiology 203:3 2005 Jun pg 589-98

Abstract

http://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Schlernitzauer%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Sar%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Favier%20FBhttp://www.unboundmedicine.com/medline/?st=M&author=Kaminski%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Bahi%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Garnier%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Fortin%20Dhttp://www.unboundmedicine.com/medline/?st=M&author=Serrurier%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Veksler%20Vhttp://www.unboundmedicine.com/medline/?st=M&author=Bigard%20AXhttp://www.unboundmedicine.com/medline/?st=M&author=Ventura-Clapier%20Rhttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Cell%20Physiol


Thyroid hormone (TH) is an important regulator of mitochondrial content and activity. As mitochondrial content and properties differ depending on muscle-type, we compared mitochondrial regulation and biogenesis by T3 in slow-twitch oxidative (soleus) and fast-twitch mixed muscle (plantaris). Male Wistar rats were treated for 21 to 27 days with T3 (200 microg/kg/day). Oxidative capacity, regulation of mitochondrial respiration by substrates and phosphate acceptors, and transcription factors were studied. In soleus, T3 treatment increased maximal oxygen consumption (Vmax) and the activities of citrate synthase (CS) and cytochrome oxidase (COX) by 100%, 45%, and 71%, respectively (P < 0.001), whereas in plantaris only Vmax increased, by 39% (P < 0.01). ADP-independent respiration rate was increased in soleus muscle by 216% suggesting mitochondrial uncoupling. Mitochondrial substrate utilization in soleus was also influenced by T3, as were mitochondrial enzymes. Lactate dehydrogenase (LDH) activity was elevated in soleus and plantaris by 63% and 11%, respectively (P < 0.01), and soleus creatine kinase was increased by 48% (P < 0.001). T3 increased the mRNA content of the transcriptional co-activator of mitochondrial genes, PGC-1alpha, and the I and IV COX subunits in soleus. The muscle specific response to thyroid hormones could be explained by a lower content of TH receptors in plantaris than soleus. Moreover, TRalpha mRNA level decreased further after T3 treatment. These results demonstrate that TH has a major effect on mitochondrial content, regulation and coupling in slow oxidative muscle, but to a lesser extent in fast muscle, due to the high expression of TH receptors and PGC-1alpha transcription factor.

Regulation of fibronectin by thyroid hormone receptors.

Lin KH, Chen CY, Chen SL, Yen CC, Huang YH, Shih CH, Shen JJ, Yang RC, Wang CS

Source

Journal of molecular endocrinology 33:2 2004 Oct pg 445-58

(My note from Wiki: insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process. Fibronectin is a high-molecular weight (~440kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Similar to integrins, fibronectin binds extracellular matrix components such as collagen.)

Abstract

Thyroid hormones regulate growth, development, differentiation, and metabolic processes by interacting with and activating thyroid hormone receptors and associated pathways. We investigated the triiodothyronine (T3) modulation of gene expression, in human hepatocellular carcinoma cell lines, via a PCR-based cDNA subtraction method. Here we present further data on one of the T3-upregulated genes, fibronectin (FN). We demonstrate that the induction of FN protein expression by T3 in TRalpha1 and TRbeta1 over-expressing cells was time and dose-dependent at the mRNA and protein levels. Blockade of protein synthesis by cycloheximide almost completely inhibited the concomitant induction of FN mRNA by T3, indicating that T3 indirectly regulates FN. Furthermore, nuclear-run on and FN promoter assay clearly can specifically increase the number of FN transcriptional demonstrated that the presence of T3 initiations. In addition, we further confirmed that the up-regulation of FN by T3 was mediated, at least in part, by transforming growth factor-beta (TGF-beta), because the induction of FN was blocked in a dose-dependent manner by the addition of TGF-beta neutralizing antibody. In an effort to elucidate the we demonstrated the involvement of the signaling pathways involved in the activation of FN by T3, mitogen activated protein kinase/c-Jun N-terminal kinase/p38 MAPK (MAPK/JNK/p38) pathway. Although T3 induces the expression of TGF-beta, neither wild-type nor dominant-negative Smad3 or Smad4 over-expression affected the activation of FN by T3. Thus, we demonstrate that T3 regulates FN gene expression indirectly at the transcriptional level, with the participation of the MAPK/JNK/p38 pathway and the TGF-beta signaling pathway but independent of Smad3/4.

http://www.unboundmedicine.com/medline/?st=M&author=Lin%20KHhttp://www.unboundmedicine.com/medline/?st=M&author=Chen%20CYhttp://www.unboundmedicine.com/medline/?st=M&author=Chen%20SLhttp://www.unboundmedicine.com/medline/?st=M&author=Yen%20CChttp://www.unboundmedicine.com/medline/?st=M&author=Huang%20YHhttp://www.unboundmedicine.com/medline/?st=M&author=Shih%20CHhttp://www.unboundmedicine.com/medline/?st=M&author=Shen%20JJhttp://www.unboundmedicine.com/medline/?st=M&author=Yang%20RChttp://www.unboundmedicine.com/medline/?st=M&author=Wang%20CShttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Mol%20Endocrinol


Thyroid hormones and mitochondria.

Authors

Goglia F, Silvestri E, Lanni A

Abstract

Because of their central role in the regulation of energy-transduction, mitochondria, the major site of

oxidative processes within the cell, are considered a likely subcellular target for the action that thyroid

hormones exert on energy metabolism. However, the mechanism underlying the regulation of basal

metabolic rate (BMR) by thyroid hormones still remains unclear. It has been suggested that these

hormones might uncouple substrate oxidation from ATP synthesis, but there are no clear-cut data to

support this idea. Two iodothyronines have been identified as effectors of the actions of thyroid

hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2). Both

have significant effects on BMR, but their mechanisms of action are not identical. T3 acts on the nucleus

to influence the expression of genes involved in the regulation of cellular metabolism and mitochondria

function; 3,5-T2, on the other hand, acts by directly influencing the mitochondrial energy-transduction

apparatus. A molecular determinant of the effects of T3 could be uncoupling protein-3 (UCP-3), while

the cytochrome-c oxidase complex is a possible target for 3,5-T2. In conclusion, it is likely that

iodothyronines regulate energy metabolism by both short-term and long-term mechanisms, and that

they act in more than one way in affecting mitochondrial functions.

The Triiodothyronine Mitochondrial Pathway

C. Wrutniak, P. Rochard, F. Casas, G. Cabello

Abstract

Numerous data show that mitochondrial activity is hormonally regulated. Besides the influence

of α-agonists, glucagon and vasopressin, several studies show that glucocorticoid, thyroid

hormone, vitamin D3 and peroxisome proliferators stimulate the activity of this organelle.

Interestingly, thyroid hormone, glucocorticoid, peroxisome proliferators and vitamin D3

receptors all belong to a common nuclear receptor superfamily. These data suggest that such

receptors could have a particular importance in the regulation of mitochondrial activity.

However, the mechanisms involved in this endocrine influence remain poorly understood. The

action of thyroid hormone, especially triiodothyronine (T3), upon the organelle has been studied,

leading to the proposition of a direct T3 mitochondrial pathway. In this paper, we present

numerous data in agreement with this hypothesis, with special reference to recent work from our

laboratory identifying a T3 binding protein in the mitochondrial matrix.

http://link.springer.com/search?facet-author=%22C.+Wrutniak%22http://link.springer.com/search?facet-author=%22P.+Rochard%22http://link.springer.com/search?facet-author=%22F.+Casas%22http://link.springer.com/search?facet-author=%22G.+Cabello%22


Modification of nucleic acid levels per mitochondrion induced by thyroidectomy or

triiodothyronine administration

T. De Leo, S. Di Meo, A. Barletta, G. Martino, F. Goglia

Summary

The authors have determined the liver mitochondrial population (number of

mitochondria/nucleus) in young rats, which has been thyroidectomized ( T¯ ) or thyroidectomized and subsequently treated with triiodothyronine (T3). They have observed that

thyroidectomy decreased such a population to 72.3% with respect to the normal one, while the T3

administration (at the dose of 10 μg/100 g body weight every second day, from day 50 to day 60

of age) restored the mitochondria number to 81.8% of normal ones.

The average levels of proteins per mitochondrion were 8.90×10−13

g in the liver of normal 60-

day-old rats. This content was doubled in T¯ rats of the same age while the levels of nucleic acids or the nucleic acid polymerase activities per mitochondrion were enhanced,

notwithstanding that the specific values (referred to mg mitochondrial protein) decreased. The T3

administration severely lowered the content of protein per mitochondrion, and this may indicate

that thyroid hormones control the normal assemblage of mitochondrial protein.

Thyroid control over biomembranes. VII. Heart muscle mitochondria from -

triiodothyronine-injected rats

Hoch, Frederic L.

1982-02

Citation: Hoch, Frederic L. (1982/02)."Thyroid control over biomembranes. VII. Heart muscle

mitochondria from -triiodothyronine-injected rats." Journal of Molecular and Cellular Cardiology 14(2):

81-90.

Abstract: Mitochondria prepared from the myocardia of rats injected with -triiodothyronine, 1 [mu]g/g

body weight daily for 3 days, were compared with those from euthyroid or hypothyroid animals. The

heart weights of the hormonetreated animals increased 37%, whereas mitochondrial yield remained

unchanged. Oxidative phosphorylation measured at 25[deg]C featured a decreased rate of

phosphorylating (State 3) respiration with normal phosphorylative efficiency (ADP: O ratio). The

http://link.springer.com/search?facet-author=%22T.+De+Leo%22http://link.springer.com/search?facet-author=%22S.+Di+Meo%22http://link.springer.com/search?facet-author=%22A.+Barletta%22http://link.springer.com/search?facet-author=%22G.+Martino%22http://link.springer.com/search?facet-author=%22F.+Goglia%22


respiratory deficit was connected with a progressive loss as the mitochondria stood in iced suspensions;

control mitochondrial respiration decreased 0.26-times as fast. The lipid composition of the heart

mitochondria of the thyrotoxic group was abnormal in that the excess of neutral lipids (probably

triglycerides) had a high content of oleoyl residues. Their phospholipid group compositions and the fatty

acyl contents of each of the phospholipid classes were similar to control compositions, in contrast to the

excess linoleoyl and decreased arachidonoyl contents of the phosphatidylcholines in the hypothyroid

group. Thus the abnormalities of heart mitochondrial function are connected with different patterns of

lipid changes in hyperthyroidism and hypothyroidism. Evidence for a relationship of organelle lipids to

the reported abnormal myocardial contractile performance in these thyroid states is discussed. [less]

DOIs: http://dx.doi.org/10.1016/0022-2828(82)90196-1

Effects of triiodothyronine on oxidative phosphorylation in immature rat brain mitochondria

1. DAVID HOLTZMAN, Ph.D., M. D. and 2. CYRIL L. MOORE, Ph.D.

Abstract

Article abstract Oxidative phosphorylation was measured polarographically in brain mitochondria

isolated from 1 to 3-week-old normal and triiodothyronine-treated rat pups. Adenosine diphosphate

(ADP)/oxygen ratios with nicotinamide-adenine dinucleotide (NAD)-linked substrates, but not with

succinate, were increased in brain mitochondria from experimental animals at each age. Control ratios

and respiratory rates were not affected. Thus, the normal maturational increase in ADP/oxygen ratios

with NAD-linked substrates is accelerated in brain mitochondria from rats treated with triiodothyronine

from birth. This effect on efficiency of oxidative phosphorylation is similar to that of thyroid hormones

on other properties of the maturing brain.

© 1977 by the American Academy of Neurology

Triiodothyronine Prevents Cardiac Ischemia/Reperfusion Mitochondrial Impairment and Cell Loss by Regulating miR30a/p53 Axis

Francesca Forini, Claudia Kusmic, Giuseppina Nicolini, Laura Mariani, Riccardo Zucchi, Marco Matteucci, Giorgio Iervasi, and Letizia Pitto

DOI: http://dx.doi.org/10.1210/en.2014-1106

Received: February 05, 2014

Accepted: July 24, 2014

Published Online: August 19, 2014

http://dx.doi.org/http:/dx.doi.org/10.1016/0022-2828(82)90196-1http://press.endocrine.org/action/doSearch?text1=Forini%2C+F&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Kusmic%2C+C&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Nicolini%2C+G&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Mariani%2C+L&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Zucchi%2C+R&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Matteucci%2C+M&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Iervasi%2C+G&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Pitto%2C+L&field1=Contribhttp://dx.doi.org/10.1210/en.2014-1106


Abstract

Mitochondrial dysfunctions critically affect cardiomyocyte survival during ischemia/reperfusion (I/R)

injury. In this scenario p53 activates multiple signaling pathways that impair cardiac mitochondria and

promote cell death. p53 is a validated target of miR-30 whose levels fall under ischemic conditions.

Although triiodothyronine (T3) rescues post-ischemic mitochondrial activity and cell viability, no data

are available on its role in the modulation of p53 signaling in I/R. Here we test the hypothesis that early

T3 supplementation in rats inhibits the post I/R activation of p53 pro-death cascade through the

maintenance of miRNA 30a expression.

In our model, T3 infusion improves the recovery of post-ischemic cardiac performance. At the molecular

level, the beneficial effect of T3 is associated with restored levels of miR-30a expression in the area at

risk (AAR) that correspond to p53 mRNA downregulation. The concomitant decrease in p53 protein

content reduces Bax expression and limits mitochondrial membrane depolarization resulting in

preserved mitochondrial function and decreased apoptosis and necrosis extent in the AAR. Also in

primary cardiomyocyte culture of neonatal rats, T3 prevents both miR-30a downregulation and p53

raise induced by hypoxia. The regulatory effect of T3 is greatly suppressed by miR-30a knockdown.

Overall these data suggest a new mechanism of T3-mediated cardioprotection that is targeted to

mitochondria and acts, at least in part, through the regulation of miR-30a/p53 axis.

Affiliations

Consiglio Nazionale delle Ricerche (CNR) Institute of Clinical Physiology (F.F., C.K., G.N., L.M., G.I., L.P),

Via G. Moruzzi 1, Pisa, Italy; Department of Pathology (R.Z., G.I.), University of Pisa, 56127 Pisa, Italy;

Scuola Superiore Sant'Anna (M.M., G.I.), Piazza Martiri della Libertà 33, 56127 Pisa, Italy; and

CNR/Tuscany Region G Monasterio Foundation (G.I.), Via G. Moruzzi 1, 56124 Pisa, Italy

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1

Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC84876/

1. François Casas1,

2. Pierrick Rochard1,

3. Anne Rodier1,

4. Isabelle Cassar-Malek1,

5. Sophie Marchal-Victorion1,

6. Rudolf J. Wiesner2,

7. Gérard Cabello1,*, and

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC84876/http://mcb.asm.org/search?author1=Fran%C3%A7ois+Casas&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Fran%C3%A7ois+Casas&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Pierrick+Rochard&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Pierrick+Rochard&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Anne+Rodier&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Anne+Rodier&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Isabelle+Cassar-Malek&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Isabelle+Cassar-Malek&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Sophie+Marchal-Victorion&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Sophie+Marchal-Victorion&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Rudolf+J.+Wiesner&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Rudolf+J.+Wiesner&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=G%C3%A9rard+Cabello&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=G%C3%A9rard+Cabello&sortspec=date&submit=Submithttp://mcb.asm.org/content/19/12/7913.full#fn-1


8. Chantal Wrutniak1

+ Author Affiliations

1. Institut National de la Recherche Agronomique, Unité d’Endocrinologie Cellulaire, Laboratoire

de Différenciation Cellulaire et Croissance, 34060 Montpellier Cedex 1, France,1 and

2. Physiologisches Institut, Universität Heidelberg, D-69120 Heidelberg, Germany2

Next Section

ABSTRACT

In earlier research, we identified a 43-kDa c-ErbAα1 protein (p43) in the mitochondrial matrix of rat

liver. In the present work, binding experiments indicate that p43 displays an affinity for

triiodothyronine (T3) similar to that of the T3 nuclear receptor. Using in organello import

experiments, we found that p43 is targeted to the organelle by an unusual process similar to that

previously reported for MTF1, a yeast mitochondrial transcription factor. DNA-binding experiments

demonstrated that p43 specifically binds to four mitochondrial DNA sequences with a high similarity

to nuclear T3 response elements (mt-T3REs). Using in organello transcription experiments, we

observed that p43 increases the levels of both precursor and mature mitochondrial transcripts and

the ratio of mRNA to rRNA in a T3-dependent manner. These events lead to stimulation of

mitochondrial protein synthesis. In transient-transfection assays with reporter genes driven by the

mitochondrial D loop or two mt-T3REs located in the D loop, p43 stimulated reporter gene activity

only in the presence of T3. All these effects were abolished by deletion of the DNA-binding domain

of p43. Finally, p43 overexpression in QM7 cells increased the levels of mitochondrial mRNAs, thus

indicating that the in organello influence of p43 was physiologically relevant. These data reveal a

novel hormonal pathway functioning within the mitochondrion, involving a truncated form of a

nuclear receptor acting as a potent mitochondrial T3-dependent transcription factor.

The regulation of mitochondrial activity by thyroid hormone is well documented. Triiodothyronine

(T3) increases the number of mitochondria (20, 24-25) and mitochondrial protein synthesis (33).

This hormone is thus considered to be a major regulator of mammalian mitochondrial biogenesis

(33). T3 also stimulates mitochondrial metabolism (46) and, in particular, oxidative phosphorylation

(48,50).

Triiodothyronine modulates the expression of aquaporin-8 in rat liver mitochondria

1. Giuseppe Calamita,

2. Maria Moreno1,

3. Domenico Ferri2,

4. Elena Silvestri1,

http://mcb.asm.org/search?author1=Chantal+Wrutniak&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Chantal+Wrutniak&sortspec=date&submit=Submithttp://mcb.asm.org/content/19/12/7913.fullhttp://mcb.asm.org/content/19/12/7913.full#sec-1http://mcb.asm.org/content/19/12/7913.full#ref-20http://mcb.asm.org/content/19/12/7913.full#ref-24http://mcb.asm.org/content/19/12/7913.full#ref-33http://mcb.asm.org/content/19/12/7913.full#ref-33http://mcb.asm.org/content/19/12/7913.full#ref-46http://mcb.asm.org/content/19/12/7913.full#ref-48http://mcb.asm.org/content/19/12/7913.full#ref-50http://joe.endocrinology-journals.org/search?author1=Giuseppe+Calamita&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Moreno&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Moreno&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Domenico+Ferri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Domenico+Ferri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Elena+Silvestri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Elena+Silvestri&sortspec=date&submit=Submit


5. Patrizia Roberti,

6. Luigi Schiavo1,

7. Patrizia Gena,

8. Maria Svelto and

9. Fernando Goglia1

+ Author Affiliations

1. Department of General and Environmental Physiology, Università degli Studi di Bari,

Via Amendola 165/A, 70126 Bari, Italy

2. 1Department of Biological and Environmental Sciences, University of Sannio, Via

Port’Arsa 11, 82100 Benevento, Italy

3. 2Department of Zoology, University of Bari, Bari, Italy

1. (Requests for offprints should be addressed to G Calamita; Email: [email protected])

Next Section

Abstract

The recent identification of aquaporin-8 (AQP8), an aquaporin (AQP) channel permeable to water and

ammonia, in the inner membrane (IMM) of rat liver mitochondria suggested a role for such AQP in

the hydration state and the metabolic function of mitochondria. Since thyroid hormone

triiodothyronine (T3) is known to modulate both the shape and the metabolic activities of liver

mitochondria, it was interesting to investigate the expression and distribution of AQP8 as well as the

osmotic water permeability of the IMM in liver mitochondria from rats in different thyroid states. By

semi-quantitative reverse transcriptase (RT)-PCR, when compared with the euthyroid counterpart,

the levels of hepatic AQP8 mRNA significantly increased in the hypothyroid state, whereas they were

strongly decreased after administration of T3. A similar pattern was seen at the protein level by

immunoblotting mitochondrial membranes. The upregulation of mitochondrial AQP8 in the

hypothyroid liver was confirmed by immunogold electron microscopy. Stopped-flow light scattering

with IMM vesicles showed no significant differences in terms of osmotic water permeability among

the IMMs in the various thyroid states. Overall, our data indicate that the T3 modulation of the AQP8

gene is a rapid downregulation of transcription. Modulation of hepatic AQP8 expression may be

relevant to the regulation of mitochondrial metabolism by thyroid hormones.

Previous SectionNext Section

Introduction

Triiodothyronine (T3) exerts significant actions on energy metabolism, with mitochondria being a

major target for its effects (Soboll 1993). Extensive changes occur in the mitochondrial compartment

in response either to thyroid hormone administration or to physiological states modulating thyroid

gland activity (e.g. cold exposure, aging, dietary changes; Goglia et al. 1999). Indeed, alterations to

the thyroid state of animals have considerable effects on the synthesis (Roodyn 1965, Goglia et al.

1988), the turnover (Gross 1971), and the functional capacity of mitochondrial components. Liver

mitochondria from hypothyroid rats have a decreased activity of membrane-associated electron

http://joe.endocrinology-journals.org/search?author1=Patrizia+Roberti&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Luigi+Schiavo&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Luigi+Schiavo&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Patrizia+Gena&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Svelto&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Fernando+Goglia&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Fernando+Goglia&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/content/192/1/111.fullmailto:[email protected]://joe.endocrinology-journals.org/content/192/1/111.full#sec-1http://joe.endocrinology-journals.org/content/192/1/111.full#abstract-1http://joe.endocrinology-journals.org/content/192/1/111.full#abstract-1http://joe.endocrinology-journals.org/content/192/1/111.full#ref-44http://joe.endocrinology-journals.org/content/192/1/111.full#ref-15http://joe.endocrinology-journals.org/content/192/1/111.full#ref-39http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-16


transport enzymes and anion carriers (Paradies et al. 1994), a failure that has been ascribed to a

lower expression of their corresponding proteins as well as to changes in the composition of the

inner membrane (Soboll et al. 1994, Schonfeld et al. 1997). Thyroid hormones are also known to

modulate both shape and metabolic efficiency of mitochondria (Jakovcic et al. 1978, Goglia et al.

1988). However, although marked differences in the shape and the number of the cristae have been

reported in the liver mitochondria of rats in different thyroid states (Jakovcic et al. 1978, Goglia et al.

1989), the molecular mechanisms underlying T3 modulation of mitochondrial morphology remain

mostly elusive. A clue to understanding such mechanisms relates to the fact that mitochondria are

well-behaved osmometers and that their shape is influenced by the movement of water

accompanying the net transport of solutes into and out of their matrix (Beavis et al. 1985).

Endocrine regulation of mitochondrial activity: involvement of truncated RXRalpha and c-Erb Aalpha1 proteins.

Authors

Casas F, Daury L, Grandemange S, Busson M, Seyer P, Hatier R, Carazo A, Cabello G, Wrutniak-Cabello C

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17:3 2003 Mar pg 426-36

Abstract

The importance of mitochondrial activity has recently been extended to the regulation of developmental processes. Numerous pathologies associated with organelle's dysfunctions emphasize their physiological importance. However, regulation of mitochondrial genome transcription, a key element for organelle's function, remains poorly understood. After characterization in the organelle of a truncated form of the triiodothyronine nuclear receptor (p43), a T3-dependent transcription factor of the mitochondrial genome, our purpose was to search for other mitochondrial receptors involved in the regulation of organelle transcription. We show that a 44 kDa protein related to RXRalpha (mt-RXR), another nuclear receptor, is located in the mitochondrial matrix. We found that mt-RXR is produced after cytosolic or intramitochondrial enzymatic cleavage of the RXRalpha nuclear receptor. After mitochondrial import and binding to specific sequences of the organelle genome, mt-RXR induces a ligand-dependent increase in mitochondrial RNA levels. mt-RXR physically interacts with p43 and acts alone or through a heterodimerical complex activated by 9-cis-retinoic acid and T3 to increase RNA levels. These data indicate that hormonal regulation of mitochondrial transcription occurs through pathways similar to those that take place in the nucleus and open a new way to better understand hormone and vitamin action at the cellular level.

Effect of thyroid hormone on the myosin heavy chain isoforms in slow and fast muscles of the rat.

Authors

Jakubiec-Puka A, Ciechomska I, Mackiewicz U, Langford J, Chomontowska H

Source

Acta biochimica Polonica 46:3 1999 pg 823-35

Abstract

http://joe.endocrinology-journals.org/content/192/1/111.full#ref-38http://joe.endocrinology-journals.org/content/192/1/111.full#ref-45http://joe.endocrinology-journals.org/content/192/1/111.full#ref-41http://joe.endocrinology-journals.org/content/192/1/111.full#ref-24http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-24http://joe.endocrinology-journals.org/content/192/1/111.full#ref-14http://joe.endocrinology-journals.org/content/192/1/111.full#ref-14http://joe.endocrinology-journals.org/content/192/1/111.full#ref-1http://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Daury%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Busson%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Hatier%20Rhttp://www.unboundmedicine.com/medline/?st=M&author=Carazo%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Jakubiec-Puka%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Ciechomska%20Ihttp://www.unboundmedicine.com/medline/?st=M&author=Mackiewicz%20Uhttp://www.unboundmedicine.com/medline/?st=M&author=Langford%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Chomontowska%20Hhttp://www.unboundmedicine.com/medline/?st=M&journal=Acta%20Biochim%20Pol


The myosin heavy chain (MHC) was studied by biochemical methods in the slow-twitch (soleus) and two fast-twitch leg muscles of the triiodothyronine treated (hyperthyroid), thyroidectomized (hypothyroid) and euthyroid (control) rats. The changes in the contents of individual MHC isoforms(MHC-1, MHC-2A, MHC-2B and MHC-2X) were evaluated in relation to the muscle mass and the total MHC content. The MHC-1 content decreased in hyperthyreosis, while it increased in hypothyreosis in the soleus and in the fast muscles. The MHC-2A content increased in hyperthyreosis and it decreased in hypothyreosis in the soleus muscle. In the fast muscles hyperthyreosis did not affect the MHC-2A content, whereas hypothyreosis caused an increase in this MHC isoform content. The MHC-2X, present only in traces or undetected in the control soleus muscle, was synthesised in considerable amount in hyperthyreosis; in hypothyreosis the MHC-2X was not detected in the soleus. In the fast muscles the content of MHC-2X was not affected by any changes in the thyroid hormone level. The MHC-2B seemed to be not influenced by hyperthyreosis in the fast muscles, whereas the hypothyreosis caused a decrease of its content. In the soleus muscle the MHC-2B was not detected in any groups of rats. The results suggest that the amount of each of the four MHC isoforms expressed in the mature rat leg muscles is influenced by the thyroid hormone in a different way. The MHC-2A and the MHC-2X are differently regulated in the soleus and in the fast muscles; thyroid hormone seems to be necessary for expression of those isoforms in the soleus muscle.

Thyroid Hormone Binding by a Component of mitochondrial membrane

Proceedings of the National Academy of Sciences of the United States of America © 1975 National

Academy of Sciences

Abstract:

The thyroid hormone, triiodothyronine, has been shown to be bound by the intranuclear

chromatin protein associated with active DNA, where it is believed to stimulate transcription.

Evidence exists that the thyroid hormones have direct action not only on nuclei, but also on

mitochondria. Therefore, specific proteins that bind thyroid hormones in the mitochondria should

be demonstrable. Mitochondria were isolated from homogenized rat livers by sedimentation

through 0.25 M sucrose solution, followed by washing four times to free them of microsomes.

Strong binding of thyroid hormones was observed in mitochondrial fractions prepared from both

the membranes and the matrix. After incubation in an ice bath with increasing amounts of

triiodothyronine with added tracer [125I]triiodothyronine, the matrix infrequently contained

specific saturable receptor sites, but usually exhibited strong ``nonspecific'' interaction. In

contrast, a protein fraction obtained from the mitochondrial membranes revealed on Scatchard

plot an association constant approximating 4 × 109 liters/M, significantly higher than that we

have obtained for isolated rat liver nuclei (about 5 × 108 liters/M). Partial purification of the

mitochondrial membrane protein resulted in pronounced diminution of ``nonspecific binding''

and a higher apparent association constant (ka greater than 1011 liters/M). The demonstration of

a triiodothyronine binding protein in the mitochondrial membrane is consistent with direct

hormone action upon mitochondria. The binding sites of nuclei and mitochondria both exhibit

saturability, and are considered to have a role in hormone action. The nuclear protein binding is

believed to influence growth, development, and functions concerned with cell maintenance,

whereas mitochondrial protein binding is probably concerned with reversible effects on energy

metabolism.

http://www.jstor.org/action/showPublisher?publisherCode=nashttp://www.jstor.org/action/showPublisher?publisherCode=nas


"Mild" Uncoupling of Mitochondria A. A. Starkov Received January 10, 1997 Recently, it was proposed that the thyroid hormone-mediated uncoupling in mitochondria is involved

in the cellular defence system against free radicals (Skulachev V.P. (1996) Quart. Rev. Biophys.

29:169-202). This phenomenon was named "mild" uncoupling. It was postulated to be a protein mediated

process controlled by several factors. The data reported during the past 40 years, pointing to

the protein-mediated uncoupling mechanism in mitochondria, are reviewed in a context of

hypothetical properties of "mild" uncoupling. The mechanism of "mild" uncoupling is suggested to be

the following: (a) mitochondria possess protein(s) that regulate the proton permeability of inner

mitochondrial membrane; (b) these proteins are regulated by binding of an unidentified low molecular- weight endogenous compound with properties resembling those of the most active artificial

uncouplers like FCCP and SF6847; (c) the interaction of this compound with its target protein(s) is

modulated by a thyroid hormone in a positive (i.e. enhancing the proton permeability) way and by sex

steroid hormones in a negative way; (e) endogenous fatty acids can attenuate the influence of both

thyroid and steroid hormones.

KEY WORDS: Uncoupling; mitochondria; free radicals; thyroid hormones; steroid hormones

Effect of Calcium Ion on Triiodothyronine Binding to Kidney Outer Mitochondrial

Membrane in vitro

KIYOSHI HASHIZUME, KAZUO ICHIKAWA AND MUTSUHIRO KOBAYASHI

Department of Gerontology, Endocrinology and Metabolism,

Shinshu University School of Medicine, Matsumoto 390

Abstract

The effect of calcium ion on 3,5,3'-triiodothyronine (T3) binding to rat kidney outer mitochondrial

membranes was examined in vitro. The outer mitochondrial membranes were prepared by using a

discontinuous sucrose density gradient centrifugation. The membrane fraction, which is enriched with

monoamine oxidase activity, contained specific binding sites for T3. Scatchard analysis of T3 binding to

outer mitochondrial membranes gave an association constant (Ka) of 0.53 •~ 1010M-1. The binding of

[125I]-T3 to the membranes was inhibited by the addition of CaCl2(0.25 •~ 10-4-2.5 •~ 10-3M). 50%

inhibition was obtained by 0.75 x 10-4M CaC12 in the presence of 0.1 mM EGTA. When outer

mitochondrial membranes were solubilized with Triton X-100, four main T3 binding activities were

isolated by a gel filtration study. On the other hand, the binding of [125I]-T3 to the solubilized T3

receptors derived from outer mitochondrial membranes was not strongly inhibited by calcium. When

outer mitochondrial membranes were preincubated in the presence of 1 mM calcium, the number of T3

binding sites in the membranes was decreased, and this was associated with an increase in the number

of T3 binding sites in the supernatants of the incubation mixture. Scatchard analysis showed that the

number of T3 binding sites in the membranes is decreased by calcium ion without any change in the

association constant. In studies with gel filtration of receptors which are released by Ca2+ from outer

mitochondrial membranes, three main T3 binding activities were isolated. Mg2+, Mn2+, Zn2+ and Cu2+

did not affect T3 binding to outer mitochondrial membranes. The results indicate that calcium ion


regulates T3 binding to the outer mitochondrial membrane through the release of T3 receptors from the

membranes.

Mol Cell Endocrinol. 2013 Oct 15;379(1-2):51-61. doi: 10.1016/j.mce.2013.06.006. Epub 2013 Jun 13.

Thyroid hormones and mitochondria: with a brief look at derivatives and analogues.

Cioffi F1, Senese R, Lanni A, Goglia F.

Author information

1Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy.

Abstract

Thyroid hormones (TH) have a multiplicity of effects. Early in life, they mainly affect development and differentiation, while later on they have particularly important influences over metabolic processes in almost all tissues. It is now quite widely accepted that thyroid hormones have two types of effects on mitochondria. The first is a rapid stimulation of respiration, which is evident within minutes/hours after hormone treatment, and it is probable that extranuclear/non-genomic mechanisms underlie this effect. The second response occurs one to several days after hormone treatment, and leads to mitochondrial biogenesis and to a change in mitochondrial mass. The hormone signal for the second response involves both T3-responsive nuclear genes and a direct action of T3 at mitochondrial binding sites. T3, by binding to a specific mitochondrial receptor and affecting the transcription apparatus, may thus act in a coordinated manner with the T3 nuclear pathway to regulate mitochondrial biogenesis and turnover. Transcription factors, coactivators, corepressors, signaling pathways and, perhaps, all play roles in these mechanisms. This review article focuses chiefly on TH, but also looks briefly at some analogues and derivatives (on which the data is still somewhat patchy). We summarize data obtained recently and in the past to try to obtain an updated picture of the current research position concerning the metabolic effects of TH, with particular emphasis on those exerted via mitochondria.

Mutat Res. 1989 Mar;211(1):171-80.

4-Quinolone antibiotics: positive genotoxic screening tests despite an apparent lack of mutation induction.

Bredberg A1, Brant M, Riesbeck K, Azou Y, Forsgren A.

Author information

1Department of Medical Microbiology, University of Lund, Malmö, Sweden.

Abstract

http://www.ncbi.nlm.nih.gov/pubmed/23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Cioffi%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Senese%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Lanni%20A%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Goglia%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed/23769708http://www.ncbi.nlm.nih.gov/pubmed/2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Brant%20M%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Riesbeck%20K%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Azou%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed/2921999


The effects of different 4-quinolone antibiotic derivatives (4-Qs) in a number of short-term tests commonly employed for the evaluation of genetic toxicity were studied. Incorporation of [3H]thymidine into mitogen-stimulated peripheral blood lymphocytes was strongly enhanced at a low concentration (1.56 micrograms/ml) for most of the tested 4-Qs, whereas DNA strand breakage in lymphoblastoid cells was evident only for ciprofloxacin (10 micrograms/ml and upwards), ofloxacin (80 micrograms/ml) and norfloxacin (160 micrograms/ml). Ciprofloxacin induced a significant amount of unscheduled DNA synthesis, but was found to be negative in a shuttle vector plasmid mutation test. Ciprofloxacin (80 micrograms/ml) did not inhibit enzymes involved in the early steps of pyrimidine biosynthesis. Cell growth was slightly depressed at a concentration of 20 micrograms/ml, becoming marked at 80 micrograms/ml. In conclusion, this study seeks to contribute to an improved evaluation of genotoxic screening test data, by focusing attention on the conflicting effects imposed by the 4-Qs on a battery of such tests.

)From Wiki: A mitogen is a chemical substance that encourages a cell to commence cell division, triggering

mitosis. A mitogen is usually some form of a protein. Mitogenesis is the induction (triggering) of mitosis, typically

via a mitogen. Mitogens trigger signal transduction pathways in which mitogen-activated protein kinase (MAPK) is

involved, leading to mitosis. B cells can enter mitosis when they encounter an antigen matching their

immunoglobulin. Mitogens are often used to stimulate lymphocytes and therefore assess immune function.

Lipopolysaccharide toxin from gram-negative bacteria is thymus-independent. They may directly activate B cells,

regardless of their antigenic specificity. Plasma cells are terminally differentiated and, therefore, cannot undergo

mitosis. Memory B cells can proliferate to produce more memory cells or plasma B cells. This is how the mitogen

works, that is, by inducing mitosis in memory B cells to cause them to divide, with some becoming plasma cells.

Mitogen-activated protein kinases (MAPK) are protein kinases that are specific to the amino acids, serine,

threonine, and tyrosine.)

Antimicrob Agents Chemother. 1987 May;31(5):774-9.

Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth.

Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF.

Abstract

Several of the new 4-quinolones significantly increase the incorporation of [3H]thymidine into the DNA of mitogen-stimulated human lymphocytes. This study suggests that ciprofloxacin inhibits de novo pyrimidine biosynthesis, thereby resulting in a compensatory increase in the uptake of pyrimidine precursors through salvage pathways, and that additional effects may affect eucaryotic cell growth. Incorporation of deoxyuridine, uridine, and orotic acid as well as thymidine was increased in the presence of ciprofloxacin, one of the antibacterially most active of the new 4-quinolones. In contrast, the uptake was decreased in very high concentrations of the drug. Culture in HAT (hypoxanthine, aminopterine, thymidine) medium, which blocks de novo thymidylate synthesis, abrogated the increase in [3H]thymidine incorporation induced by ciprofloxacin. Ciprofloxacin also failed to increase the uptake of [14C]hypoxanthine or leucine, indicating a selective effect on pyrimidine and not on purine nucleotide biosynthesis. N-(Phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine nucleotide biosynthesis, also increased [3H]thymidine incorporation in phytohemagglutinin-stimulated lymphocytes in a fashion similar to ciprofloxacin. The growth of several cell lines was partially inhibited by ciprofloxacin at 20 micrograms/ml and completely inhibited at 80 to 160 micrograms/ml. Growth inhibition by ciprofloxacin could not be restored by the addition of uridine to the medium. Chromosome breaks, gene amplification, or other genetic alterations could not be detected in human lymphocytes incubated with up to 25 micrograms of ciprofloxacin per ml.

Antimicrob Agents Chemother. 1987 May;31(5):768-73.

http://en.wikipedia.org/wiki/Chemical_substancehttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Mitogen-activated_protein_kinasehttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Antibodyhttp://en.wikipedia.org/wiki/Lymphocytehttp://en.wikipedia.org/wiki/Lipopolysaccharidehttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Gram-negative_bacteriahttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Specificity_(tests)http://en.wikipedia.org/wiki/Plasma_cellhttp://en.wikipedia.org/wiki/Cellular_differentiationhttp://en.wikipedia.org/wiki/Memory_B_cellhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Kinasehttp://en.wikipedia.org/wiki/Amino_acidshttp://www.ncbi.nlm.nih.gov/pubmed/3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Pardee%20AB%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Schlossman%20SF%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Tedder%20TF%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed/3606076


4-Quinolone drugs affect cell cycle progression and function of human lymphocytes in vitro.

Forsgren A, Schlossman SF, Tedder TF.

Abstract

Most antibacterial agents do not affect human lymphocyte function, but a few are inhibitory. In contrast, a pronounced increase in the incorporation of [3H]thymidine in the presence of 4-quinolones was observed in these studies. The uptake of [3H]thymidine into DNA (trichloroacetic acid precipitable) was significantly increased in phytohemagglutinin-stimulated human lymphocytes when they were exposed to eight new 4-quinolone derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619, A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25 micrograms/ml for 5 days. Four less antibacterially active 4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic acid) stimulated [3H]thymidine incorporation only at higher concentrations or not at all. Kinetic studies showed that incorporation of [3H]thymidine was not affected or slightly inhibited by ciprofloxacin 2 days after phytohemagglutinin stimulation but was increased on days 3 to 6. The total incorporation of [3H]thymidine from day 1 to day 6 after phytohemagglutinin stimulation was increased by 42 to 45% at 5 to 20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine incorporation was also seen when human lymphocytes were stimulated with mitogens other than phytohemagglutinin. Ciprofloxacin added at the start of the culture had a more pronounced effect on [3H]thymidine incorporation than when added later. In spite of the apparent increase in DNA synthesis, lymphocyte growth was inhibited by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis showed that ciprofloxacin inhibited progression through the cell cycle. In addition, immunoglobulin secretion by human lymphocytes stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited by approximately 50% at 5 micrograms of ciprofloxacin per ml. These results suggest that the 4-quinolone drugs may also affect eucaryotic cell function in vitro, but additional studies are needed to establish an in vivo relevance.

(Note: are there increased thymidines in mitochondria, thereby leading to mutations and cell death?)

Scand J Infect Dis Suppl. 1989;60:39-45.

Effect of ciprofloxacin on human lymphocytes--laboratory studies (Wow, talk about a turnaround and retraction of his previous studies . . . ).

Forsgren A1, Bredberg A, Riesbeck K.

Author information

1Department of Medical Microbiology, University of Lund, Malmö General Hospital, Sweden.

Abstract

4-Quinolones affect mammalian cellular functions in vitro in several ways. Inhibition of cell proliferation differ widely among 4-quinolones. Ciprofloxacin is one of the most antiproliferative inhibiting cell growth with about 30% at 20 mg/l. Genotoxicity tests with 4-quinolones are probably "false" positive due to an increased [3H]-thymidine uptake not related to DNA damage. Ciprofloxacin at 10 mg/l and up causes significant DNA strand breaks which seemingly are quickly repaired and not causing mutations or cancerogenesis. Ciprofloxacin at 5 mg/l inhibits immunoglobulin production but the growth factor interleukin 2 (IL-2) is increased by 4-quinolones at the same concentration and hyperinduced at higher

http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed?term=Schlossman%20SF%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed?term=Tedder%20TF%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed/2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Riesbeck%20K%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed/2667107


concentrations. Thus the effects are very contradictory. Increased IL-2 may contribute to CNS side effects.

Drug Saf. 1992 May-Jun;7(3):214-22.

Mutagenicity of quinolone antibacterials.

Fort FL.

Author information

Department of Toxicology, Abbott Laboratories, Abbott Park, Illinois.

Abstract

The literature is summarised on the activity of quinolone antibacterial compounds in assays which are commonly used for risk assessment of new pharmaceuticals. These include assays for DNA damage, sister chromatid exchanges, chromosome aberrations and mutation induction. The general pattern of activity exhibited by these compounds is induction of DNA damage in both prokaryotic and eukaryotic cells, and induction of mutations in DNA repair-proficient bacteria and at the thymidine kinase locus in mammalian cells. They do not appear as a class to induce mutations at the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) or Na+,K(+)-ATPase loci or to cause chromosome aberrations. It is suggested that these actions may be the result of interference with eukaryotic topoisomerase and that this interference differs in some respects from the topoisomerase interference caused by certain antitumour compounds. The postulated mechanism of action has important implications for assessment of risk from consumption of quinolone antibacterials. The risk of adverse genotoxic events should vary directly with the concentration of drug reaching the intracellular enzyme target and the affinity of the drug for the target. Results of carcinogenicity studies conducted to date with the quinolone antibacterials suggest minimal risk from long term consumption of the newer, second-generation compounds.

Links: Mitochondria, Thyroid, FQ’s,

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC171543/ Ciprofloxacin Does Not Inhibit Mitochondrial

Functions but Other Antibiotics Do

http://www.ncbi.nlm.nih.gov/pubmed/1503668http://www.ncbi.nlm.nih.gov/pubmed?term=Fort%20FL%5BAuthor%5D&cauthor=true&cauthor_uid=1503668http://www.ncbi.nlm.nih.gov/pubmed/1503668http://www.ncbi.nlm.nih.gov/pmc/articles/PMC171543/


http://www.ncbi.nlm.nih.gov/pubmed/6257866 Influence of diet composition on serum

triiodothyronine (T3) concentration, hepatic mitochondrial metabolism and shuttle system activity in

rats

http://www.jbc.org/content/277/18/15225.full Active Site Mutation in DNA Polymerase γ Associated

with Progressive External Ophthalmoplegia Causes Error-prone DNA Synthesis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760005/ Bactericidal Antibiotics Induce Mitochondrial

Dysfunction and Oxidative Damage in Mammalian Cells

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271032/ Inherited Mitochondrial Diseases of DNA

Replication

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235551/ Mitochondrial Medicine for Aging and

Neurodegenerative Diseases

http://aac.asm.org/content/56/8/4046.full Adverse Effects of Antimicrobials via Predictable or

Idiosyncratic Inhibition of Host Mitochondrial Components

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041094 Mitochondrial

Topoisomerase I is Critical for Mitochondrial Integrity and Cellular Energy Metabolism

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175594/ Mitochondrial Biogenesis and Turnover

http://3dmoleculardesigns.com/3DMD-Files/2GoodsellMitochondria.pdf Miniseries: Illustrating the

Machinery of Life: Mitochondrion

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778844/ A mitochondrial protein compendium

elucidates complex I disease biology

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219168/ Effect of 3,5-di-iodo-L-thyronine on the

mitochondrial energy-transduction apparatus

http://ajpcell.physiology.org/content/302/2/C463.long Triiodothyronine induces UCP-1 expression and

mitochondrial biogenesis in human adipocytes

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC209375/ Effect of triiodothyronine on mitochondrial

energy coupling in human skeletal muscle

http://www.jbc.org/content/239/9/3062.full.pdf Action and Metabolism of Thyroid Hormones and Iodine-Donating Substances: Site of Action in the Respiratory Chain. “ We now show that when electron transport associated with cytochrome b is prevented, an effect of thyroxine on mitochondria is also blocked. From these data we may conclude that electron transport in this region is essential for the action of thyroxine, I2 and ICN.”

http://www.ncbi.nlm.nih.gov/pubmed/6257866http://www.jbc.org/content/277/18/15225.fullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760005/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271032/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235551/http://aac.asm.org/content/56/8/4046.fullhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041094http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175594/http://3dmoleculardesigns.com/3DMD-Files/2GoodsellMitochondria.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778844/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219168/http://ajpcell.physiology.org/content/302/2/C463.longhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC209375/http://www.jbc.org/content/239/9/3062.full.pdf


(Need to Google This Title for Link): Thyroid Economy—Regulation, Cell Biology, Thyroid Hormone

Metabolism and Action: The Special Edition: Metabolic Effects of Thyroid Hormones Thyroid Hormone

Effects on Mitochondrial Energetics, Mary-Ellen Harper and Erin L. Seifert

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1186541/ The Influence of Thyroxine Administered in

vivo on the Transmembrane Protonic Electrochemical Potential Difference in Rat Liver Mitochondria

http://link.springer.com/article/10.1007%2FBF01458354#page-1 Effects of Iodine upon the Structure

and Function of Mitochondria. This is an excellent paper; I’m not sure where I got the paper, but it

should be on the internet somewhere. A must read for anyone interested in iodine and thyroxine

mechanisms of action. Look up author for her other papers as well. Conclusions were the following:

“The similarity between the effects of iodine compounds and the thyroxine observed in vivo and in vitro

gives us reason to suggest that: 1. De-iodination of the thyroid hormone constitutes a necessary step in

the realization of its effect upon the structure and function of mitochondria. 2. The active components

in the molecule of the thyroid hormone, as regards its biochemical effect, are the iodine atoms. 3. The

possible places of interaction between the membrane and the iodine ions (I +) are the negative charges

fixed in the membrane. 4. Neutralization of the charges of the mitochondrial membrane is the major

event leading to changes in its resistance, conductivity, permeability and coupling mechanisms of the

oxidative phosphorylation”.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931645/pdf/amjpathol00388-0058.pdf STUDIES ON

MITOCHONDRIA: T

Thyroid Hormones and Mitochondria abstracts · hormones: presence and action of steroid and thyroid...

Documents

Transcript of Thyroid Hormones and Mitochondria abstracts · hormones: presence and action of steroid and thyroid...