Mitochondria-Targeted Protective Compounds in Parkinson's and Alzheimer's Diseases - Med & Cellular...

Review ArticleMitochondria-Targeted Protective Compounds inParkinsons and Alzheimers Diseases

Carlos Fernndez-Moriano, Elena Gonzlez-Burgos, and M. Pilar Gmez-Serranillos

Department of Pharmacology, Faculty of Pharmacy, University Complutense of Madrid, 28040 Madrid, Spain

Correspondence should be addressed to M. Pilar Gomez-Serranillos; [email protected]

Received 30 December 2014; Revised 25 March 2015; Accepted 27 March 2015

Academic Editor: Giuseppe Cirillo

Copyright 2015 Carlos Fernandez-Moriano et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlightedfunctions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calciumhomeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis andmetabolismof various keymolecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesisof ageing-related neurodegenerative disorders including Parkinsons disease and Alzheimers disease. Mitochondria-targetedprotective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in theprevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement ofmitochondrial dysfunction in Parkinsons and Alzheimers diseases, with particular attention to in vitro and in vivo studies onpromising endogenous and exogenous mitochondria-targeted protective compounds.

1. Introduction

Mitochondria are spherical cytoplasmic organelles with asymbiotic origin that are present in all eukaryotic cells.Structurally, mitochondria consist of two compositions andfunctionally different phospholipid membranes referred toas the outer membrane and the inner membrane and twoaqueous compartments, the intermembrane space and themitochondrial matrix. The outer membrane encloses theentire structure; it has higher content in lipids (over 60%)and it contains porins and a large multiprotein translocasecomplex allowing the passage to ions and larger molecules.The inner membrane surrounds the mitochondrial matrixand it invaginates to form cristae that increase total surfacearea. In addition, the inner membrane has lipid content over20% and it is only permeable to small uncharged molecules.Both membranes are separated by the aqueous compartmentintermembrane space, located between them [1, 2].Moreover,mitochondria contain their own DNA (mDNA) held inthe mitochondrial matrix; the human mDNA is a double-stranded circular genome made up of 16,569 base pairs of

DNA that encodes 13 proteins, 22 transfer RNAs (tRNAs), and2 ribosomal RNAs (rRNAs) [3]. Functionally, mitochondriaplay a vital role in regulating both metabolic and apoptoticsignaling pathways.Their main function is to produce energyas adenosine triphosphate (ATP) at the mitochondrial elec-tron transport chain (ETC) in the inner membrane, throughthe cellular process of oxidative phosphorylation (OXPHOS).The mitochondrial ETC consists of four integral membraneoxidation-reduction electron and proton pump protein com-plexes (complex I, NADH:ubiquinone oxidoreductase; com-plex II, succinate dehydrogenase; complex III, ubiquinone-cytochrome oxidoreductase; complex IV, cytochrome oxidase) and an ATP synthase (complex V) which catalyzesADP conversion to form ATP [4]. In addition, mitochondriaparticipate in other series of functions, including regulationof cellular calcium homeostasis, balance between ROS pro-duction and detoxification (i.e., superoxide anion (O

2

) andthe highly reactive hydroxyl radical (OH)), mediation of theprocess of programmed cell death (apoptosis), and synthesisand metabolism of endogenous compounds such as steroids,heme groups, and fatty acids [5].

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015, Article ID 408927, 30 pageshttp://dx.doi.org/10.1155/2015/408927

2 Oxidative Medicine and Cellular Longevity

Consistent evidence suggests that mitochondrial failureis associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinsonsdisease and Alzheimers disease. Mitochondria-targeted pro-tective compounds that prevent or minimize mitochondrialdysfunction constitute potential therapeutic strategies in theprevention and treatment of these central nervous systemdiseases [6, 7]. This paper provides an overview of theinvolvement ofmitochondrial dysfunction in Parkinsons andAlzheimers diseases, with particular attention to in vitro andin vivo studies on promising endogenous and exogenousmitochondria-targeted protective compounds.

2. Parkinsons Disease and Mitochondria-Targeted Protective Compounds

2.1. Parkinsons Disease (PD). Parkinsons disease is a chronicprogressive disorder characterized pathologically by the lossof dopaminergic neurons located in the substantia nigrapars compacta, and, to a lesser extent, in putamen, caudate,and globus pallidus and by the formation of intracellularprotein inclusions of mainly alpha-synuclein (named asLewy bodies) in the remaining neurons [8, 9]. The firstclinical description was published in 1817 by the EnglishphysicianDr. Parkinson in his work An Essay on the ShakingPalsy [10]. Parkinsons disease is the second most commonneurodegenerative disorder after Alzheimers disease whichaffects more than 6.3 million people over usually the ageof 60 worldwide. Regarding epidemiology, this age-relatedcentral nervous system disease appears to be slightly morecommon in whites than blacks and Asian people, in menthan inwomen, and in some geographical regions (i.e., China,India, and USA) [1113]. The most relevant clinical featuresinclude tremor, bradykinesia, rigidity, and dystonia; however,in addition to these characteristicmotor signs and symptoms,neuropsychiatric and other nonmotor manifestations suchas depression, cognitive impairment, anxiety, and psychosishave been also described [8, 9, 14]. Although the exactcausal factors of Parkinsons disease remain unknown, severalresearch studies point to specific genetic mutations andenvironmental factors [15, 16]. It has been estimated thataround 510 in every 100 people suffering from Parkinsonsdisease are associated with gene mutations. Scientifics haveidentified at least 13 gene mutations, among which one couldhighlight those in the genes SNCA (synuclein, alpha non-A4 component of amyloid precursor), PARK2 (Parkinsonsdisease autosomal recessive, juvenile 2), PARK7 (Parkinsonsdisease autosomal recessive, early-onset 7), PINK1 (PTEN-induced putative kinase 1), and LRRK2 (leucine-rich repeatkinase 2) [15].The SNCA gene encodes for the protein alpha-synuclein, which is a key component of Lewy bodies; thePARK2 gene encodes for the E3 ubiquitin ligase parkin,which is implied in mitochondrial maintenance; the PARK7gene encodes for the antioxidant protein DJ-1; PINK 1gene encodes for a serine/threonine-protein kinase with aprotective mitochondrial role. Alterations of SNCA, PARK2,PARK7, and PINK1 genes are involved in the early-onsetParkinsons disease (this is diagnosed before being 50 years

old) [1720].The LRRK2 gene, which encodes for the proteindardarin, has been associated with the late-onset Parkinsonsdisease [21]. The rest, around 95%, of diagnosed Parkinsonsdisease cases are sporadic, in which environmental factorssuch as pesticides and dietary factors, among others, seemto play a crucial role. Researchers have identified severalcommon pesticides that their exposure may increase the riskof developing Parkinsons disease among which rotenone,paraquat, dithiocarbamates (i.e., maneb, ziram), pyrethroids(i.e., deltamethrin), organochlorine (dieldrin), imidazoles(i.e., triflumizole, benomyl), and 2,2-dicarboximides (i.e.,folpet, aptan) are included [22, 23]. Regarding dietary factors,both dietary patterns or/and dietary nutrients that may pro-tect or may increase against to suffer from Parkinsons diseasehave been reported. As an example, in a case control studyperformed during ten years for establishing the influence ofminerals, vitamins, and fats in the etiology of Parkinsons dis-ease, an association between a high intake of a combinationof iron and manganese and the development of Parkinsonsdiseasewas found [24]. On the other hand, a large prospectivestudy performed over fifteen years with 49 692 men and81 676 women revealed that the high intake of fruit, vegeta-bles, legumes, whole grains, nuts, fish, and poultry, the lowintake of saturated fat, and the moderate intake of alcohol areprotective dietary patterns against Parkinsons disease [25].

2.1.1. Mitochondrial Dysfunction in Familial PD. As we havepreviously commented, around 510% of Parkinsons dis-ease cases involve gene products. Mutations in ATP13A2(PARK9), DJ-1 (PARK7), parkin (PARK2), and PTEN-induced putative kinase 1 (PINK1) (PARK6) are associatedwith autosomal recessive PD and mutations in -synucleingene and leucine-rich repeat kinase 2 gene (LRRK2) areimplicated in autosomal dominant PD (see Figure 1) [16].

Mutations in the ATP13A2 gene (PARK9), encodingfor a lysosomal type 5P-type ATPase, cause a hereditaryrare juvenile onset autosomal recessive Parkinsonism withdementia named as Kufor-Rakeb syndrome. This particularParkinsons form, characterized by supranuclear gaze palsy,dystonia, pyramidal signs, and cognitive impairment, wasfirst evidenced in 2006 in members of a nonconsanguineousChilean family. The neuronal damage associated with muta-tions in this gene is related to alterations inmitochondria andlysosomes functions and divalent cation regulation [2628].

DJ-1 mutations on chromosome 1p36 cause autosomalrecessive early-onset PD and its pathological mechanismseems to be linked with mitochondrial fragmentation andmitochondrial structural damage and consequently defects inthe mitochondrial function of dopaminergic cells [29, 30].

Mutations in the parkin gene product, which is an ubiqui-tin ligase, lead to an early-onset familial Parkinsons diseaseand its first description dates in the year 1998. Experimentalstudies have determined that the pathology of parkin isassociated with alterations in the mitochondrial recogni-tion, transportation, and ubiquitination and with mitophagyimpairment [31, 32].

Mutations in themitochondrial serine/threonine-proteinkinase PINK1 result in alterations in the mitochondrial

Oxidative Medicine and Cellular Longevity 3

III

IIIIV

V

Alpha-synuclein

PINK1

ATP production

PINK1

ROS

PINK1

Parkin

Mitochondrialpotential

LRRK2

LRRK2

Mitochondrialdysfunction

DJ-1

DJ-1

DJ-1

Figure 1: The role of gene products in Parkinsons disease.

morphology and function (defects in complex I activity)and they are strongly associated with a form of autosomalrecessive early-onset Parkinsons disease [33, 34].

Mutations in the protein -synuclein, which is the maincomponent of Lewy bodies (it represents 1% of total cytosolicprotein of brain cells), have been reported to play a keyrole in the pathogenesis of autosomal dominant early-onsetParkinsons disease. Particularly, two mutations in the alpha-synuclein gene (A30P and A53T) have been identified whichlead to the formation of pathogenic pore-like annular andtubular protofibrils. These mutations inhibit the activity ofcomplex I and induce mitochondrial fragmentation, causingmitochondrial dysfunction [35, 36].

Mutations in the gene encoding leucine-rich repeatkinase 2 (LRRK2) are related to autosomal dominant Parkin-sons disease form. The most common mutation is G2019Sthat accounts for 5-6% of familial cases of Parkinsons disease.Experimental studies have identified different pathogenicmechanisms for altered LRRK2 that involve inflammationprocesses, oxidative stress, and mitochondrial dysfunction,among others. Focusing on this last pathogenic mechanism,mutations in LRRK2 cause mitochondrial fragmentation anda downregulation in mitochondrial homeostasis (reductionin mitochondrial membrane potential and ATP production)[37, 38].

2.1.2. Mitochondrial Dysfunction in Sporadic PD. Around95% of diagnosed Parkinsons disease cases are sporadic.One of the proposed mechanisms for the dopaminergicneurons degeneration in sporadic Parkinsons disease cases isrelated to an excessive production of reactive oxygen species(ROS) that leads to oxidative stress situation. An excess of

ROS causes the oxidative modification of macromolecules(lipids, proteins, and DNA) leading to cell damage andeven cell death. The pathological effect of ROS is alsoinvolved in a reduction of ATP (adenosine triphosphate)production, in an increase of iron levels, and in an increaseof intracellular calcium levels and alterations in mitochon-drial respiratory chain complexes function. In addition tooxidative stress mechanism, protein misfolding, aggregation,and deposition have been reported as other common patho-logical mechanisms in Parkinsons disease. A dysfunction inthe ubiquitin-proteasome-system (UPS) and the autophagy-lysosomal pathway (ALP) as evidenced in a reduction ofproteasome and autophagy activities and in postmortembrains of patients suffering from this neurodegenerativedisease has been demonstrated [3943].

2.1.3. PostmortemPDBrain Tissues, ExperimentalModels, andCell-Based Models. Many evidences from postmortem PDbrain tissues, experimental models, and cell-based modelshave demonstrated the involvement of mitochondria dys-function in the pathogenesis of both familial and sporadicParkinsons disease.

The first evidence of the relationship between mitochon-dria and Parkinsons disease dates from the second half ofthe twentieth century when the postmortem brain analysisof some drug abusers of intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), who have developed aprogressive and irreversible parkinsonism, revealed a signifi-cant nigrostriatal degeneration. MPTP easily passes throughthe blood-brain barrier; it is oxidized and transformed into1-methyl-4-phenylpyridinium (MPP+) and within neurons


MPP+ inhibits the complex I (NADH-quinone oxidore-ductase) of the electron transport chain, resulting in anenhanced reactive oxygen species (ROS) generation (i.e.,hydroxyl radicals, superoxide anion radical) and a decrease inenergy supply (ATP production) [44].Many lines of evidencehave further demonstrated complex I deficiency or impair-ment in the cortical brain tissue, frontal cortex, striatum,skeletal muscle, and platelets of patients with Parkinsonsdisease [40, 45, 46]. In addition to complex I, other studieshave reported that a deficiency in the activity of complexII (succinate ubiquinone oxidoreductase) and complex III(ubiquinol-cytochrome C oxidoreductase) is also associatedwith the pathogenesis of Parkinsons disease. Complex IIIinhibition, as what happens with complex I, causes an over-production of ROS, leading to oxidation of lipids, proteins,and DNA and it finally triggers to cell death [47, 48]. More-over, ROS mediates the mitochondrial-dependent apoptosisby inducing mitochondrial permeability transition, releasingof cytochrome c, activation of caspase-3 and caspase-9,translocation of Bax to mitochondria, and the activation ofc-Jun N-terminal kinase (JNK) and p38 mitogen-activatedprotein kinase (p38 MAPK) in the cytosol [49, 50].

The neurotransmitter dopamine has been also relatedto the pathogenesis of Parkinsons disease. In vitro experi-mental researches on neuronal cell types and isolated brainmitochondria and in vivo studies using different animalmodels and postmortem brain studies in Parkinsons diseasehave demonstrated that dopamine oxidation and reactivedopamine quinone oxidation products inducemitochondrialrespiration uncoupling and cause ATP levels reduction andinactivate proteasomal activity, among other effects, whichcontribute to mitochondrial dysfunction [5157]. The roleof tetrahydrobiopterin (BH4) in Parkinsons disease etiologyis also remarkable; BH4 is an obligatory cofactor for thedopamine synthesis enzyme tyrosine hydroxylase and it ispresent selectively in monoaminergic neurons in the brain.It has been suggested as an endogenous molecule thatcontributes to the dopaminergic neurodegeneration throughan inhibition of the activities of complexes I and IV of theelectron transport chain (ETC), together with a release ofmitochondrial cytochrome C and a reduction of mitochon-drial membrane potential [58].

There are other studies which involve calcium excitotoxi-city and nonexcitotoxicity relatedmechanisms in the etiologyof Parkinsons disease. Alterations in calcium influx in neu-rons via L-type voltage-dependent channels and N-methyl-D-aspartate (NMDA) receptors may lead to an excitotoxiccellular calcium accumulation that can cause mitochon-drial dysfunction by reducing ATP production, activatingmitochondrial permeability transition, increasing ROS gen-eration, and inducing mitochondrial-dependent apoptosis[59, 60]. Other circumstances, not ordinarily toxic, havebeen reported to contribute to mitochondrial dysfunction.Hence, Sheehan et al. (1997) showed using mitochondriallytransformed cells (cybrids) that the capacity to sequestratecalciumwas lower in patients with Parkinsons disease than incontrol subjects, suggesting that this homeostasis alterationcould increase neurons cell death [61].

Regarding familial Parkinsons disease, mutations in sev-eral genes previously reported (Parkin, PINK1, DJ-1, -synu-clein, and LRRK2) which encode for mitochondrial proteinshave been identified to contribute to mitochondrial dysfunc-tion [62, 63].

There are different neurotoxins including rotenone, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydop-amine (6-OHDA), and paraquat, among others, which havebeen extensively used as Parkinsons disease experimentalmodels to mimic the neuropathology of this neurodegener-ative disorder in both in vitro (i.e., human neuroblastomaSK-N-SH cells) and in vivo (animals models such as rats,mice) investigations and, consequently, to help establishneuroprotective strategies. Rotenone, an insecticide extractedfrom the roots of Derris spp. and Lonchocarpus spp. (Legu-minosae family), acts by inhibiting the mitochondrial res-piratory chain complex I [64]. Paraquat (1,1-dimethyl-4,4-bipyridinium dichloride), which is a quaternary nitrogenherbicide used to control weed growth, has been reported toincrease ROS generation and induce-synuclein fibril forma-tion [65]. The 1-methyl-1,2,3,6-tetrahydropyridine (MPTP),a byproduct obtained during the chemical synthesis of ameperidine analog, is metabolized in the brain to the toxiccompound MPP+ which inhibits complex I of the electrontransport chain [44]. The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA), via intracerebral infusion,causes the irreversible loss of nigrostriatal dopaminergicneurons by inducing ROS production and inhibiting complexI and complex IV of the electron transport chain [66].

2.2. Mitochondria-Targeted Protective Compounds in PD.Endogenous and exogenous compounds are in continuinginvestigation as mitochondria-targeted agents to prevent ortreat Parkinsons disease (Figure 2). Table 1 reports com-pounds that have been demonstrated to be promising agentsin the protection of mitochondrial dysfunction in differentParkinsons disease models. Hence, among the endogenouscompounds investigated so far, the hormone melatonin, theneuropeptide cocaine, and amphetamine regulated transcript(CART), the ursodeoxycholic acid, the mitoQ (mitoquinonemesylate), and the -lipoic acid can be highlighted. Thehormone melatonin has been shown to exert in vivo mito-chondrial protective action in MPTP-induced mice model,6-OHDA rat model, and rotenone-induced rat model bymaintaining mitochondrial membrane potential, increasingantioxidant enzymatic (i.e., SOD, CAT) and nonenzymaticlevels (i.e., glutathione), inhibiting ROS overproduction,increasing ATP production, decreasing calcium concentra-tion levels, and enhancing mitochondrial complex I activ-ity [6771]. The neuropeptide cocaine and amphetamineregulated transcript (CART) protected mitochondrial DNAand cellular proteins and lipids of human neuroblastomaSH-SY5Y cells, HEK293 cells, and cultures of cortical andhippocampal neurons exposed to hydrogen peroxide [72].The ursodeoxycholic acid (one of the secondary bile acids)and the mitoQ (mitoquinone mesylate) acted as antiapop-totic agent in human neuroblastoma SH-SY5Y cells treatedwith SNP and 6-OHDA, respectively [73, 74]. The -lipoic


III

IIIIV

V

Mitochondrial DNA

DNA damage

Apoptosis

Green tea polyphenols, melatonin

Mitochondrial

Mitochondrial

permeabilitytransition pore (MPTP)

membrane potentialMelatonin, lycopene

respiratory chain

Hesperidin, quercetin, -lipoic acid,xyloketal B, melatonin

Neuropeptide cocaine, amphetamineregulated transcript (CART)

Chunghyuldan, curcumin, hesperidin, green teapolyphenols, pyruvate, quercetin, -lipoic acid,xyloketal B, melatonin, rosmarinic acid, harmalol,harmine, lycopene, glutamoyl diester of curcumin

Chunghyuldan, curcumin, pyruvate, silymarin,baicalein, tyrosol, hesperidin, green tea polyphenols,quercetin, -lipoic acid, xyloketal B, melatonin,rosmarinic acid, harmalol, harmine, glutamoyldiester of curcumin

Ursodeoxycholic acid, licorice, Panax ginseng,MitoQ (mitoquinone mesylate), caffeic acid phenethyl ester,salvianic acid A, salvianolic acid B, protocatechuic acid,umbelliferone, esculetin, osthole, Chunghyuldan, curcumin,silymarin, baicalein, tyrosol, hesperidin, green tea polyphenols,pyruvate, isoborneol, piperine, tetramethylpyrazine, astaxanthin

ROS

ROS Mitochondrial

ATP production

Ca2+

Mitochondrial Ca2+

Cytosolic Ca2+

Antioxidant system

Figure 2: Mechanisms of mitochondrial dysfunction and mitochondria-targeted drugs that have produced beneficial effect in PD models.

acid has been evaluated as mitochondrial-targeted protec-tive compound in several in vitro and in vivo Parkinsonsdisease models (i.e., PC12 cells, SK-N-MC cells, and ratmodel; toxins as MPP(+) and rotenone); this organosulfurcompound derived fromoctanoic acid protectsmitochondriaby inhibiting ROS production, increasing glutathione levels,andmaintainingmitochondrialmembrane potential [7578].Pyruvate has also been demonstrated in in vitro studies thatmaintains mitochondrial membrane potential and inhibitsROS generation and nuclear translocation of NF-kappaB aswell as mitochondrial apoptotic pathway [79, 80].

Several natural products from medicinal plants, bothisolated compounds and extracts, have been demonstrated inin vitro and in vivo studies to exert promising mitochondrialprotection. As extracts, it has been reported that berries richin anthocyanidins and proanthocyanidins protect mitochon-dria from rotenone-induced changes in the respiratory chain[118]. The silymarin, which is a standardized extract of themilk thistle seeds, maintained mitochondrial integrity andfunction and inhibited mitochondrial apoptotic pathway inMPP(+)-induced ratmodel [119]. Green tea polyphenols havebeen also evidenced to inhibit mitochondrial apoptotic path-way (increasing Bcl2 and decreasing caspase-3 activity) andto maintain mitochondrial membrane potential, to inhibitROS production and calcium concentration levels [120]. Thelicorice (root of Glycyrrhiza glabra) inhibited dopaminergicapoptotic cell death as evidenced in the increase in Bcl2levels and in the decrease in Bax levels, caspase-3 activity,cytochrome c release, and JNK andMAP activities in amodelof 6-OHDA-induced Parkinsons disease [121]. The waterextract of Panax ginseng also inhibited apoptosis MPP(+)-induced in the human neuroblastoma SH-SY5Y cells bydecreasing Bax levels, caspase-3 activity, and cytochromerelease and increasing Bcl2 levels [122].

The herbal medicine Chunghyuldan inhibited caspase-3,ROS generation and maintained mitochondrial membranepotential in 6-OH Parkinsons disease model [123]. Amongisolated natural products, highlight those with polyphenolstructure.The polyphenol resveratrol has been demonstratedin in vitro primary fibroblasts cultures from patients withparkin mutations (PARK2) to regulate mitochondrial energyhomeostasis as evidenced in the increment of complex Iactivity, citrate synthase activity, basal oxygen consumption,and ATP production and in the decrement of lactate content[111]. The polyphenol hesperidin inhibited mitochondrialapoptotic pathway (increased Bcl2 levels and decreased Bax,caspase-3, and caspase-9 activities and inhibited cytochromec release), maintained mitochondrial membrane potential,inhibited ROS production, and increased glutathione levelsin in vitro human neuroblastoma SK-N-SH cells model ofrotenone-induced Parkinsons disease [98]. Quercetin res-cued toxic-induced defects in mitochondria in in vitro andin vivo experiments. Quercetin inhibited ROS generation andmaintained mitochondria membrane potential in rotenone-induced rat model [108]. Moreover, quercetin decreased theproduction of superoxide radicals and inhibited the expres-sion of the inducible nitric oxide synthase protein expressionin in vitro glial-neuronal system model of MPP(+)-inducedParkinsons disease [109]. The flavonoid baicalein inhibitedin vitro apoptotic mitochondrial cell death and maintainedmitochondrial integrity and function in both SH-SYTY andPC12 cells in 6-OHDA and rotenone Parkinsons diseasemodels as evidenced in the decrease in caspase-3, caspase-7, caspase-9, and JNK activities and in the maintenanceof mitochondrial membrane potential, increment of ATPcontent and reduction of ROS production [8284]. Thetyrosol protected CATH.a cells against MPP(+)-toxicity byinhibiting apoptotic cell death via activation of PI3K/Akt


Table1:Parkinsons

diseasea

ndmito

chon

dria-ta

rgeted

protectiv

ecom

poun

ds.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Acetyl-L-carnitin

eQuaternary

ammon

ium

Invitro

human

neurob

lasto

maS

K-N-M

Ccells

mod

elof

roteno

ne-in

ducedPD

Maintenance

ofmito

chon

drialintegrityandfunctio

n:mito

chon

drialbiogenesis

RO

Sgeneratio

n[65]

Astaxanthin

Non

provitamin

Acaroteno

id

MPP

(+)-indu

cedmou

semod

elIn

vitro

human

neurob

lasto

maS

K-N-SHcells

mod

elof

MPP

+-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xand-synuclein

caspase-3

[81]

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

6-OHDA-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

l;maintainmito

chon

drialredox

activ

ity[82]

Baicalein

Flavon

oid

Invitro

ratadrenalph

eochromocytom

aPC12cells

mod

eland

isolatedratb

rain

mito

chon

driaof

roteno

neindu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3andcaspase-7

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nintracellularA

TPprod

uctio

n

[83]

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

6-OHDA-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lInhibitio

nof

them

itochon

drialapo

ptoticpathway:


p-c-JunN-te

rminalkinase

(JNK)

[84]

Caffeicacid

phenethyleste

rPh

enoliccompo

und

6-OHDA-indu

cedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:


cytochromec

release

Maintenance

ofmito

chon


n

[85]

Prim

arycultu

reso

fcerebellarg

ranu

leneuron

6-OHDA-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway,

caspase-3

cytochromec

release

[86]

CNB-001

Pyrazolederiv

ativeo

fcurcum

in

MPT

P-indu

cedrodent

PDmod

elMaintenance

ofno

rmalmito

chon

drialm

orph

ologyandsiz

e[87]

Invitro

human

neurob

lasto

maS

K-N-SHcells

mod

elof

roteno

ne-in

ducedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3andcaspase-9

cytochromec

release

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

l

[88]


Table1:Con

tinued.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Curcum

inPo

lyph

enol

PC12

cells

mutantA

53T-synuclein-in

ducedcelldeath

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:


cytochromec

release

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n

[89]

Mou

sebrainandthe1RB

3AN27

(N27)ratdo

paminergic

neuron

alcelllin

emod

elof

buthionine

sulfo

ximine-indu

cedPD

Maintenance

ofmito

chon


n:activ

ities

ofcomplex

Ioxidatived

amagetoproteins

glutathion

e

[90]

DL-3-n-

butylphthalid

e(N

BP)

Synthetic

compo

und

basedon

L-3-n-bu

tylphthalid

e

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

MPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nglutathion

e

[91]

Echinacosid

ePh

enylethano

idglycoside

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

H2O

2-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway

[92]

Edaravon

ePy

razolederiv

ative

Roteno

ne-in

ducedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

xMaintenance

ofmito

chon


n:RO

Sgeneratio

n

[93]

Esculetin

Cou

marin

MPT

P-indu

cedmiceP

Dmod

elInhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3

[94]

Ginseno

sideR

ePanaxatriolsapon

inPINK1

nullcells

Reversingthed

eficitincomplex

IVactiv

ity:

LR

PPRC

,Hsp90,and

Hsp60

levels

[95]

Glutamoyld

ieste

rof

curcum

inPo

lyph

enol

Mou

sebrainmito

chon

driaindu

ced-peroxynitrite

PDMaintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[96]

Harmalol

Beta-carbo

line

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

SNAP-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[97]

Harmine

Beta-carbo

line

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

SNAP-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[97]

Hesperid

inPo

lyph

enol

Invitro

human

neurob

lasto

maS

K-N-SHcells

mod

elof

roteno

ne-in

ducedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba


cytochromec

release

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nglutathion

e

[98]


Table1:Con

tinued.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Isob

orneol

Mon

oterpeno

idalcoho

lIn

vitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

6-OHDA-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3

cytochromec

release

[99]

Kaem

pferol

Flavon

oid

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

eland

prim

aryneuron

sofrotenon

e-indu

cedPD

Au

toph

agy

[100]

-Lipoica

cid

Organosulfur

compo

undderiv

edfro

moctano

icacid

Invitro

ratadrenalph

eochromocytom

aPC12cells

mod

elof

MPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[75]

Roteno

ne-in

ducedratP

Dmod

elMaintenance

ofmito

chon


n:mito

chon

drialcom

plex

Iactivity

glutathion

e[76]

Invitro

human

neurob

lasto

maS

K-N-M

Ccells

mod

elof

roteno

ne-in

ducedPD

Maintenance

ofmito

chon


n:mito

chon

drialbiogenesis

RO

Sgeneratio

n[77]

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

PD

Maintenance

ofmito

chon


n:mito

chon

drialcom

plex

Iactivity

glutathion

e[78]

Lycopene

Caroteno

id

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

MPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nlip

idperoxidatio

nintracellularA

TPprod

uctio

nmito

chon

drialD

NAcopy

numbersandmito

chon

drialR

NA

transcrip

tlevels

[101]

Roteno

ne-in

ducedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

cytochromec

release

Maintenance

ofmito

chon


n:lip

idperoxidatio

nSO

Dactiv

ityglutathion

e

[102]

MPT

P-indu

cedmiceP

Dmod

el

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lantio

xidant

enzymelevels

intracellularA

TPprod

uctio

n

[67]

Roteno

ne-in

ducedratP

Dmod

el

Maintenance

ofmito

chon


n:RO

Sgeneratio

nglutathion

eSO

Dandcatalase

activ

ities

[68]


Table1:Con

tinued.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Melaton

inHormon

eRo

teno

ne-in

ducediso

latedratb

rain

mito

chon

driaPD

mod

elMaintenance

ofmito

chon


n:Ca

2+levels

RO

Sgeneratio

n[69]

6-OHDA-indu

cedratP

Dmod

elMaintenance

ofmito

chon


n:mito

chon

drialcom

plex

Iactivity

[70]

MPP

(+)-indu

cediso

latedratliver

mito

chon

driaandstr

iatal

synaptosom

esPD

mod

elMaintenance

ofmito

chon


n:mito

chon

drialcom

plex

Iactivity

[71]

Mito

Q(m

itoqu

inon

emesylate)

In

vitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

6-OHDA-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

xDrp1

[73]

N-Acetylcysteine

Aminoacid

deriv

ativeH

2O2andtoxicq

uino

nesd

erived

from

dopamine-indu

cedrat

PDmod

el

Maintenance

ofmito

chon


n:mito

chon

drialrespiratory

activ

ityNa+

,K+-AT

Pase

activ

ity[103]

Neuropeptidec

ocaine

andam

phetam

ine

regulatedtranscrip

t(C

ART

)

Peptide

Invitro

human

neurob

lasto

maS

H-SY5

Y,HEK

293cells,and

cultu

reso

fcorticalandhipp

ocam

paln

eurons

ofH

2O2-indu

ced

PD

Maintenance

ofmito

chon


n:protectio

nof

mito

chon

drialD

NA(m

tDNA),cellu

larp

roteins,

andlip

ids

[78]

Osth

ole

Cou

marin

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

MPP

(+)-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3

cytochromec

release

[104]

Piperin

eAlkaloid

6-OHDA-indu

cedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba


cytochromec

release

[105]

Polyhydroxylated

fullerene

deriv

ative

C(60)(OH)(24)

In

vitro

human

neuroblasto

mac

ellsmod

elof

MPP

(+)-indu

ced

PD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nactiv

ities

ofcomplexes

Iand

IIoxidatived

amagetoDNAandproteins

[106]

Protocatechu

icacid

Polyph

enol

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

MPP

(+)-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2caspase-3

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nglutathion

e

[107]


Table1:Con

tinued.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Pyruvate

Organicacid

Invitro

human

neurob

lasto

maS

K-N-SHcells

mod

elof

H2O

2-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[79]

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

elof

dopamine-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

np53

nu

clear

translo

catio

nof

NF-kapp

aBInhibitio

nof

them

itochon

drialapo

ptoticpathway

[80]

Quercetin

Biofl

avon

oid

Roteno

ne-in

ducedratP

Dmod

elMaintenance

ofmito

chon


n:RO

Sgeneratio

nmaintainmito

chon

drialm

embranep

otentia

l[108]

Invitro

glial-n

euronalsystem

mod

elof

MPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:indu

ciblen

itricoxides

ynthasep

rotein

expressio

nsuperoxide

radicals

[109]

Rapamycin

Macrolid

e6-OHDA-indu

cedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-9

cytochromec

release

Maintenance

ofmito

chon


n:lip

idperoxidatio

nSO

DandGSH

-PX

[110]

Resveratrol

Polyph

enol

Invitro

prim

aryfib

roblastscultu

resfrom

patientsw

ithparkin

mutations

(PARK

2)

Maintenance

ofmito

chon


n:complex

Iactivity

citrates

ynthasea

ctivity

basaloxygenconsum

ption

mito

chon

drialA

TPprod

uctio

nlactatec

ontent

[111]

Rosm

arinicacid

Polyph

enol

Invitro

MES

23.5do

paminergicc

ellsmod

elof

6-OHDA-indu

cedPD

.

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

n[112]

Salvianica

cidA

Polyph

enol

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

MPP

(+)-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

x[113]

Salviano

licacid

BPo

lyph

enol

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

6-OHDA-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3

cytochromec

release

[114]


Table1:Con

tinued.

Com

poun

dClasso

fcom

poun

dParkinsons

mod

elMechanism

sRe

ferences

Sesamin

Lign

anIn

vitro

glial-n

euronalsystem

mod

elof

MPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:indu

ciblen

itricoxides

ynthasep

rotein

expressio

nsuperoxide

radicals

[22]

Tetram

ethylpyrazine

Pyrazine

MPT

P-indu

cedratP

Dmod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3

cytochromec

release

[115]

Tyrosol

Phenoliccompo

und

MPP

(+)-indu

cedCA

TH.acells

PDmod

el

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

l;maintainintracellularA

TPprod

uctio

nInhibitio

nof

them

itochon

drialapo

ptoticpathway:

(i)activ

ationof

PI3K

/Akt

signalling

pathway

[116]

Umbelliferone

Cou

marin

MPT

P-indu

cedmiceP

Dmod

elInhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3

[94]

Ursod

eoxycholic

acid

Second

arybileacids

Invitro

human

neurob

lasto

maS

H-SY5

Ycells

mod

elof

SNP-indu

cedPD

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2Ba

xcaspase-3,caspase-7,andcaspase-9

cytochromec

release

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nglutathion

e

[74]

XyloketalB

Triterpenoid

Invitro

ratadrenalph

eochromocytom

a(PC

12)cellsmod

eland

Caenorhabditiseleg

anso

fMPP

(+)-indu

cedPD

Maintenance

ofmito

chon


n:maintainmito

chon

drialm

embranep

otentia

lRO

Sgeneratio

nglutathion

e

[117]


signaling pathway and by maintaining ATP production andmitochondria membrane potential [116]. The caffeic acidphenethyl ester inhibited 6-OHDA-induced mitochondrialapoptotic pathway in in vitro and in vivomodels [85, 86].Thecurcumin polyphenol derived from the spice turmeric acts asmitochondrial antiapoptotic agent through the inhibition ofcaspase-3 and caspase-9 activities and cytochrome c releaseand it also protects mitochondrial integrity and function viaROS production inhibition and complex I activity enhance-ment [89, 90]. In addition to curcumin, its synthetic pyra-zole derivative compound, CNB-001, has been also studied,which avoids rotenone-inducedmitochondrial damage in thehuman neuroblastoma SK-N-SH cells by inhibiting mito-chondrial apoptotic pathway and maintaining mitochondrialstructure [87, 88]. Glutamoyl diester of curcumin has alsobeen shown to maintain mitochondrial membrane potentialand to inhibit ROS production in mouse brain mitochon-dria induced-peroxynitrite Parkinsons disease model [96].Salvianic acid A and salvianolic acid B isolated from Salviaspp. as well as protocatechuic acid afford in vitro protectionthrough antiapoptotic pathway [107, 113, 114]. The flavonoidkaempferol exerts antiparkinsonian effect via autophagy[100] and rosmarinic acid maintains mitochondria protec-tion by maintaining mitochondrial membrane potential anddecreasing ROS production [112].

Other natural products with mitochondrial protectiveeffect are the coumarins umbelliferone, esculetin, and ostholewhich in in vitro and in vivo Parkinsons disease modelshave been demonstrated to possess antiapoptotic propertieson mitochondria [94, 104]. Other compounds that exertprotection via inhibition of the mitochondrial apoptoticpathway are the monoterpenoid alcohol isoborneol [99],the alkaloid piperine [105], the pyrazine tetramethylpyrazine[81], and the nonprovitamin A carotenoid astaxanthin [115].On the other hand, the -carboline alkaloids harmalol andharmine maintained mitochondria membrane potential anddecreased ROS generation in PC12 cells exposed to S-nitroso-N-acetyl-DL-penicillamine (SNAP) [97]. Moreover,the triterpenoid xyloketal B also maintained mitochon-dria membrane potential and decreased ROS generationand it increased glutathione levels in in vitro rat adrenalpheochromocytoma (PC12) cells and Caenorhabditis elegansof MPP(+)-induced PD [117]. Furthermore, the carotenoidlycopene inhibited macromolecular mitochondrial damage(lipids, DNA, and proteins), overproduction of ROS, ATPfailed production, and cytochrome c release in MPP(+)-induced human neuroblastoma SK-N-SH cells and rotenone-induced rat model [101, 102].

3. Alzheimers Disease and Mitochondrial-Targeted Protective Compounds

3.1. Alzheimers Disease. Alzheimers disease (AD) is a neu-rodegenerative disease characterized by progressive cognitivedecline leading to complete need for care within several yearsafter clinical diagnosis [124]. AD is the most common formof dementia, being the most prevalent neurodegenerativedisease (followed by Parkinsons disease), and accounts for

approximately 65% to 75% of all dementia cases. It has beenestimated that Alzheimers disease affects over 44 millionpeople worldwide, mainly after the age of 65 years [125, 126].The incidence of AD augments with age in an exponentialmanner and its prevalence increases from 3% among indi-viduals aged 6574 to almost 50% among those 85 or older;these numbers can be translated to the extremely high healthcare costs thatAD represents [127]. In addition, because of theaging of the population, it is expected that the prevalence willquadruple by 2050, which means 1 in 85 persons worldwidewill be living with the disease [128].

AD is a progressive neurodegenerative disease with amarked late onset (late diagnosis as well) and mainly charac-terized by progressive decline of cognitive functions, mem-ory, and changes in behavior and personality [129, 130].The two major pathophysiological hallmarks that have beenobserved in postmortem brains of AD patients include extra-cellular -amyloid protein (A) deposits in the form of senileplaques and intracellular deposition of the microtubule-associated protein tau as neurofibrillary tangles, especiallyabundant in the regions of the brain responsible for learningand memory. These features have been linked to an abnor-mally enhanced neuronal loss in this condition, especiallyaffecting cholinergic neurons and consequently leading to areduction in the levels of the neurotransmitter acetylcholinein the hippocampus and cortex areas of brains of ADpatients. Moreover, AD has also been associated with theloss of synapses, synaptic function, inflammatory responsesinvolving glial cells, and mitochondrial abnormalities [131133].

Considering AD pathogenesis, multiple etiological fac-tors including genetics, environmental factors, diet, andgeneral lifestyles have to be taken into account [134]. Most ofthe cases of AD are believed to be sporadic and their causalfactors are still unknown for the vast majority of patients;on the other hand, genetic factors cause about 2% of all ADcases and include mutations in APP (A protein precursor),presenilin-1 and presenilin-2 genes, and polymorphisms inapolipoprotein allele E4 [135, 136].

Due to the complex and not fully understood etiopathol-ogy of AD, no available drug has been shown to completelyprotect neurons in AD patients, and there is a continuoussearch for new compounds and therapeutic tools. Thereare two possible conceptual approaches to the treatment ofAD. The first one is a symptomatic treatment that tries tominimize tertiary cognitive symptoms and protects fromfurther cognitive decline; it is the most common therapeutictendency and drugs such as tacrine, donepezil, and rivastig-mine have been used with this purpose with limited efficacy.Another approach is the treatment addressed to prevent theonset of the disease by sequestering the primary progenitorsor targets, to reduce the secondary pathologies of the disease,to slow disease progression, or to delay onset of disease, bypreventing or attenuating neuronal damaging factors [137,138]. With regard to this, compounds that exert activityagainst oxidative stress andmitochondrial dysfunction inAD(as discussed below) deserve to be considered as potentialtherapeutic options.


During the last two decades, consistent evidences haveproposed oxidative stress as a crucial pathogenic mechanismunderlying AD [139]. Oxidative stress (OS) occurs whenthe production of reactive oxygen species (ROS) exceedsthe antioxidant enzymatic and nonenzymatic cellular mech-anisms. Actually, the -amyloid peptide A

142 (insolubleform), which forms the senile plaques, exerts neurotoxicityinvolving OS in AD. Particularly, this A

142 has the abilityto produce ROS, mainly hydrogen peroxide, when it reactswith transition metal ions present in senile plaques [140].As a result of OS, accumulated oxidative damage to lipids,proteins, and nucleic acids in postmortem studies of brainsof patients with AD has been identified: advanced glycationend-products (AGEs), advanced lipid peroxidation end-products, nucleic acid oxidation, carbonyl-modified neuro-filament protein, and free carbonyls [141]. The brain ismore susceptible to OS than other organs because of a lowantioxidative protection system, which allows for increasedexposure of target molecules to ROS; the higher level of ROS,together with neuroinflammation and excessive glutamatelevels, is proposed to contribute to neuronal damage anddeath in AD [142].

3.1.1.Mitochondrial Dysfunction inAD. Mitochondria are theprimary source of ROS, and oxidative damage to mitochon-drial components precedes damage to any other cellular com-ponent during the development of neurodegenerative dis-eases [143]. Actually, mitochondrial dysfunction has largelybeen demonstrated as one of the main key cytopathologiesof AD [144, 145]. Numerous evidences suggest the involve-ment of -amyloid protein deposits in the mitochondrialdysfunction found in AD as a plausible mechanism for itsneurodegenerative effects [146148]. In support of this, it hasbeen shown that cells depleted of endogenousmDNA lackingfunctional electron transport chains (ETC) are resistant toA toxicity [149]; also, a reduced respiratory capacity andlow cytochrome oxidase activity were found in isolatedmitochondria exposed to A [150, 151]; transgenic miceexpressing mutant APP (amyloid protein precursor) genesexhibit mitochondrial dysfunction, and an AD transgenicmouse line presents early expression of genes encodingmito-chondrial proteins and ETC subunits, as an initial cellularchange in AD pathology [152].

Mitochondria have been shown to be a direct site ofA accumulation in AD neurons, and various experimentalmodels of AD were used by researchers to verify the effectof that specific accumulation on cell death [153]. Actually,Manczak et al. proved an association between mutant APPderivatives (A monomers and oligomers, such as A

140and A

142) and mitochondria in cerebral cortex slices fromTg2576 mice and N2a cells expressing mutant APP. Suchaccumulation supposes an increase in mitochondrial ROSproduction together with a reduced Cyt C oxidase activity,thus relating in vivo oxidative stress and impaired mitochon-drial metabolism to the toxic effects of A peptides [154].Further, Devi et al. demonstrated that the mitochondrialdysfunction in human AD brain is associated with theabnormal accumulation of APP across the mitochondrial

import channels. In postmortem evaluations, it was evidencedthat nonglycosylated full-length and C-terminal truncatedAPP had been accumulated exclusively in the protein importchannel of mitochondria of AD brains (specially higheraccumulation in AD-vulnerable regions, such as cortex,hippocampus, and amygdala), by forming stable complexeswith the outer membrane translocase and/or the inner mem-brane translocase; the effect of such association could inhibitthe entry of nuclear encoded Cyt C oxidase protein, thusdiminishing its activity in mitochondria and increasing thelevels of H

2O2.The higher the level of arrestedmitochondrial

APP, the worse the mitochondrial dysfunction [155].What ismore, a recent study indicated thatmitochondria-

targeted A142 accumulation is the necessary and sufficient

condition for A-mediated mitochondrial impairments andderived cellular death. In an in vitromodel ofmice hippocam-pal cell line (HT22 cells), an exogenous A

142 treatmentcaused a deleterious alteration in mitochondrial morphologyand function, which was blocked by a clathrin-mediatedendocytosis blocker; besides, specific mitochondria-targetedaccumulation of A

142 in HT22 cells using a mitochondria-targeting sequence reproduced the same morphological andfunctional alterations of mitochondria as those observed inAPP mutant mice model and the previous A

142-treatedHT22 cells. Mitochondria-mediated apoptotic cell deathwas observed in both models, thus implying that no othersignaling alteration induced by A plays a more relevant rolein cell death than its mitochondrial toxicity [156].

In general, mitochondrial dysfunction in AD is essen-tially characterized by diminution in complex IV activity(cytochrome c oxidase), decline in other enzymes of tricar-boxylic acids cycle, andmutations tomDNA.Themechanismthat underlies the complex IV defect is not clearly known,but a study on SK-N-SH cells exposed to A-inducedtoxicity showed a decrease in mDNA encoded complexIV subunits, at both the mRNA and protein levels; thisfinding suggests a possible relationship between decreasedcomplex IV activity and mDNA perturbation [157]. Resultsfrom cybrids studies also imply that AD is characterizedby specific mDNA mutations that correlate with defects incertain mitochondrial respiratory complexes. These changesgenerate an increased production of oxidant species and freeradicals, such as hydrogen peroxide. In turn, a deficiencyin energy metabolism and ATP generation is a seriousconsequence of impaired mitochondrial function [158, 159].In addition, deficiency in scavenging mitochondrial freeradicals may similarly contribute to the excessive oxidativedamage in the affected brain regions in AD. For instance,decreased mitochondrial MnSOD expression level has beenfound in AD patients as well as decreased Coenzyme Qin peripheral tissues and brains [160, 161]. Therefore, arelationship between the mitochondrial dysfunction and theoxidative stress situation is established.

Neurodegeneration and synaptic degradation in AD areprimarily mediated by defective mitochondrial biogenesisand axonal transport of mitochondria [162]. Normal mito-chondrial dynamics, an essential function inmaintaining cellviability, is likewise impaired in AD. Disturbances affectingthe balance of fusion and fission processes trigger serious


mitochondrial changes and lead to cellular perturbations,such as apoptosis. Recent studies have found altered levelsof mitochondrial fusion (including MNF-1/2 and OPA1) andfission (FIS1) proteins in AD hippocampal tissues, meaningdecreased fusion and increased fission processes; mitochon-drial fission proteinDLP1 has also been found to be decreasedin hippocampal neurons [163]. Moreover, mitochondrial cal-cium overload is another feature of mitochondrial dysfunc-tion inAD;Ahas been shown to cause calciumoverload thatthen causes increased free radical accumulation and provokesthe formation of mitochondrial transition pore (mPTP), thusleading to exacerbation of cytoplasmic calcium and eventualneuronal death [164].

Further, mitochondria play a pivotal role in aging andsenescence, contributing to neural dysfunction with age.They are actually the main cellular organelle implicated inthe process of neuronal apoptosis, which takes place in anexcessive manner in AD brains [165]. The fact that manyneurons undergo apoptosis in AD is evidenced by the pres-ence of high levels of activated proapoptotic proteins suchas caspase-3 and Bax in neurons that exhibit neurofibrillarytangle pathology [166].

Concerning AD models of study, unfortunately, there isno animal model so far that replicates all the major aspectsof AD pathology and symptoms, andmodels based on postu-lated disease pathways are widely used to explore biologicaltargets [167]. Regarding the investigation of the effects ofcompounds onmitochondrial dysfunction, rodent transgenicmodels are very common for reproducing the mitochon-driopathy features in AD. For instance, an APP (amyloidprecursor protein) mice transgenic model demonstratedan accelerated upregulation of the apoptotic-related factorsinvolved in mitochondria-mediated apoptosis, such as Baxand caspase-3 [168]. Similarly, isolated mitochondria fromAPPSW mice (expressing the Swedish familial mutation inAPP gene) presented an abnormally reduced mitochondrialrespiratory rate, mitochondrial membrane potential (MMP)disruption, increased ROS generation, and lower ATP levels[169]. APP/PS1 transgenic mice include mutations both inAPP and in presenilin-1 genes and show similar mitochon-drial characteristics [170]. Other models even express moremutations, such as 3xTg-ADmousemodel that includes threemutant human genes: APPswe, presenilin-1 (PS1M146V), andtau protein (tau P301L); in this model, MMP loss and highercaspases 3 and 9 activations are observed [171].

However, most of the works assessing mitochondrialdefects in AD are still performed on toxin-induced invitro models. With this respect, rat primary neurons inculture exposed to A

142 oligomers reproduced the gen-eration of mPTP in mitochondrial membrane with sub-sequent calcium overload, the MMP loss, and release ofcytochrome C, thus leading to cell death via mitochondrial-mediated apoptosis [172]. Mouse neuroblastoma N2a cellscotransfected with Swedish mutant APP and 9 deletedpresenilin-1 (N2a/Swe.9) recapitulated similar loss of mito-chondrial integrity and function and evidenced increasedmitochondrial apoptotic pathway, with a higher Bax/Bcl2ratio and augmented caspase-3 activity [173]. Recent studieshave employed cybrid neurons resulting from incorporating

platelet mitochondria from AD patients into mitochondrialDNA-depleted neuronal cells (SH-SY5Y cell line); this modeldemonstrates changes in length and density of mitochon-dria, imbalanced mitochondrial fission, and fusion dynamics(altered expression and distribution of DLP1 and Mfn2proteins), together with reduced mitochondrial function andenergy metabolism [174].

Therefore, it has been suggested that a substance of exoge-nous or endogenous origin that is able to reverse any of theaforementioned mitochondrial deficits may facilitate a betterneuronal health and then be of interest of study as a potentialactive compound in AD therapy [175]. In fact, mitochondrialmedicine is emerging as a field of research focused on thefinding of therapeutic strategies to enhance mitochondrialfunction in aging and in those neurodegenerative diseasesin which it has been shown to be impaired [176178]. Thisavenue of investigation has led to the discovery of severalagents directly targeted to mitochondria that are able to delayor revert themitochondrial impairments associated toAD; allavailable information on these compounds is reviewed belowand collected in Table 2 and schematized in Figure 3.

3.2. Mitochondria-Targeted Protective Compounds in AD

3.2.1. Synthetic Compounds. Several mitochondria-targetedantioxidants have been designed by conjugating the lipophilictriphenylphosphonium (TPP+) cation to an antioxidantmoiety, such as coenzyme Q (CoQ), obtaining as a resultcompounds like MitoQ [219]. Due to its chemical nature,MitoQ takes advantage of the large MMP for reaching highconcentrations in mitochondria and, unlike isolated CoQ,it is an effective antioxidant in the absence of functionalETC [220, 221]. McManus et al. demonstrated that MitoQ iseffective in preventing loss of spatial memory and delayingthe early neuropathology in a triple transgenic mouse modelof AD; they evaluated its effect on mitochondrial deficiencyand found that MitoQ avoided the MMP drop and reducedthe apoptosis in cortical neurons by a decrease in caspase-3 activity [171]. Another study employed a Caenorhabditiselegansmodel overexpressing human A end evidenced thatMitoQ exerted protective effects on lifespan and A-inducedparalysis and markedly ameliorated the depletion of mito-chondrial lipid cardiolipin and increased the mitochondrialETC function by protecting complexes IV and I; however, itwas not able to reduce the A-induced mitochondrial DNAoxidative damage [201].

Recently, Szeto developed a series of small, cell-perme-able antioxidant peptides (SS peptides) that are known toprotect mitochondria from oxidative damage [222]. SS31 (H-D-Arg-Dmt-Lys-Phe-NH2) is one of them and presents asequence motif that allows it to target mitochondria. In anA2535-induced AD model of mice hippocampal neurons,

SS31 restored axonal transport ofmitochondria and displayedpromising protection and maintenance of mitochondrialfunction, proved by an increase in the number of healthy andintact mitochondria and a reduction in the levels of fissionproteins, matrix protein, andCypD [162]. Similar results werefound by Calkins et al. [211]. Manczak et al. also revealed


Table2:Alzh

eimersdiseasea

ndmito

chon

dria-ta

rgeted

protectiv

ecom

poun

ds.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

17--Estr

adiol

Estro

gen

Invitro

isolatedmito

chon

driafro

mpostm

ortem

human

ADand

SFADbrains

Activ

ationof

mito

chon

drialaconitase

[179]

Acetyl-L-carnitin

eAminoacid

Invivo

F344

ratm

odel

Resto

ratio

nof

intactmito

chon

drialm

orph

ologyand

preventio

nfro

mage-relatedmito

chon

driald

ecay

[180]

Acteoside

Glycosid

eIn

vitro

A2535-in

ducedSH

-SY5

Yhu

man

neuroblasto

mac

ells

mod

el

Maintenance

ofmito

chon


n:RO

Sprod

uctio

nMMPloss

Cy

tCrelease

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

x/Bc

l-2ratio

caspase-3cle

avage

[181]

ASS234

Aminew

ithcomplex

structure

Invitro

A142-in

ducedSH

-SY5

Yhu

man

neuroblasto

mac

ells

mod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

levelsof

cleaved

caspases

3and9

levelsof

proteolysedPA

RP[182]

Caffeine

Alkaloid

Invivo

APP

swmicem

odel

Maintenance

ofmito

chon


n:resto

ratio

nof

mito

chon

drialrespiratory

rate,

maintenance

ofMMP

RO

Sprod

uctio

nAT

Plevels

[169]

Colostrinin

Polypeptide

Invitro

A-in

ducedhu

man

SH-SY5

YandratP

C12cells

mod

elMaintenance

ofmito

chon


n:mito

chon

drialH

2O2prod

uctio

n[183]

Crud

ecaffeine

Alkaloid

Invitro

prim

aryneuron

sfrom

J20mou

selin

e

Maintenance

ofmito

chon


n:AT

Plevels

RO

Sprod

uctio

nInhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3activ

ity

[184]

Cyclo

sporin

A

Invitro

isolatedcorticalmito

chon

driafro

mmAPP

-Ppif

/transgenicmice

Maintenance

ofmito

chon


n:inhibitio

nof

mPT

Pop

ening

Ca

2+bu

fferin

gcapacity

[185]

D609

Tricyclodecan-9-yl-

xantho

genate

Invitro

A142-in

ducediso

latedbrainmito

chon

driamod

el(fr

omgerbils)

Maintenance

ofmito

chon


n:levelsof

proteincarbon

yls

levelsof

protein-bo

undHNE

levelsof

3-NT

Cy

tCrelease

Maintenance

ofGSH

/GSSGratio

GST,G

Px,and

GRactiv

ities

[186]

DAPT

Com

plex

structure

ofbu

tyleste

rIn

vitro

N2a/A

PP695andN2a/A

PPsw

ecellsmod

elsMaintenance

ofmito

chon


n:stabilizatio

nof

norm

alMMPandAT

Plevels

[187]

Dim

ebon

Tetrahydrocarboline

Invitro

A2535-exposed

isolatedratb

rain

mito

chon

dria

Maintenance

ofmito

chon


n:inhibitio

nof

mPT

Pop

ening

[188]


Table2:Con

tinued.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

Edaravon

ePy

razolin

one

Invitro

N2a/Swe.

9cells

mod

el

Maintenance

ofmito

chon


n,MMP

RO

Sprod

uctio

nCy

tCrelease

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

x/Bc

l2ratio

Ca

spase-3activ

ation

[173]

Ergothioneine

2-Mercaptoh

istidine

trim

ethylbetaine

Invitro

A2535-in

ducedPC

12ratp

heochrom

ocytom

acells

mod

el

Maintenance

ofmito

chon


n:MMPloss

Inhibitio

nof

them

itochon

drialapo

ptoticpathway,

ratio

Bax/Bc

l-XL

caspase-3activ

ation

[189]

Gels

olin

Peptide

Invitro

A142-in

ducedratepithelialcells

mod

elMaintenance

ofmito

chon


n:increase

inmito

chon

drialcom

plex

IVactiv

ity[19

0]

Genistein

Phytoestrogen

Mito

chon

drialfractionof

postm

ortem

human

ADbrains

mito

chon

drialN

a/K-AT

Pase

activ

ity[191]

GLP

-1(9-36)

amide

Peptide

Invitro

sliceso

fhippo

campu

sfrom

APP

/PS1

mice

Maintenance

ofmito

chon


n:abno

rmalmito

chon

drialSOlevels

[192]

Glutathione

Tripeptid

eIn

vitro

A-in

ducedhu

man

HCN

-1Acells

mod

elMaintenance

ofmito

chon


n:mito

chon

drialm

embraned

epolarization

[193]

Invitro

isolatedmito

chon

driafro

mpostm

ortem

human

ADand

SFADbrains

Activ

ationof

mito

chon

drialaconitase

[179]

GypenosideX

VII

Phytoestrogen

Invitro

A2535-in

ducedPC

12cells

mod

el

Maintenance

ofmito

chon


n:resto

ratio

nof

norm

alMMP

Cy

tCrelease

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3activ

ationandcle

avage

PA

RPcle

avage

[194]

JHX-

4,HK-

2,and

HK-

4

Invitro

A-in

ducedhu

man

SH-SY5

Ycells

mod

elPreventio

nfro

mMnC

l 2-indu

cedlossof

mito

chon

drialactivity

[195]

Lipo

icacid

Organosulfur

compo

undderiv

edfro

moctano

icacid

Invivo

F344

ratm

odel

Resto

ratio

nof

intactmito

chon

drialm

orph

ologyand

preventio

nfro

mage-relatedmito

chon

driald

ecay

[180]

Invitro

fibroblastsfro

mADpatients

Maintenance

ofmito

chon


n:NMP-indu

cedmito

chon

drialoxidativ

estre

ssInhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

xandcaspase-9levels

[196]


Table2:Con

tinued.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

Invitro

A2535-indu

cedmou

semicroglialB

V2cells

mod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

activ

ationof

Bcl-2

antiapo

ptoticpathways

Ba

xmRN

Alevel

Bc

l-2expressio

ncaspase-3activ

ity

[197]

Invitro

A2535-indu

cedrath

ippo

campaln

eurons

mod

el

Maintenance

ofmito

chon


n:resto

ratio

nof

MMPloss

attenu

ationof

respira

tory

chaincomplexes

AT

Plevels

[198]

Melaton

inHormon

eIn

vivo

APP

/PS1

transgenicmice

Maintenance

ofmito

chon


n:resto

ratio

nof

mito

chon

drialrespiratory

rates

MMP

AT

Plevels

[170]

Invivo

APP

swmicem

odel

Maintenance

ofmito

chon


n,resto

ratio

nof

mito

chon

drialrespiratory

rate

maintenance

ofMMP

RO

Sprod

uctio

nAT

Plevels

[169]

Invitro

isolatedmito

chon

driafro

mpostm

ortem

human

ADand

SFADbrains

Activ

ationof

mito

chon

drialaconitase

[179]

Invivo

APP

transgenicmicem

odel

Maintenance

ofmito

chon


n,SO

Dactiv

ityInhibitio

nof

them

itochon

drialapo

ptoticpathway,

Ba

x,caspase-3,andPar-4expressio

ns

[168]

Methylene

blue

Phenothiazine

Invivo

C57B

L/6mice

Maintenance

ofmito

chon


n,mito

chon

drialcom

plex

IV(CytCoxidase)

activ

ityMAO

activ

ity

[199]

Invitro

A-in

ducedmou

seneurob

lasto

maN

2acells

mod

el

Maintenance

ofmito

chon


n,abno

rmalexpressio

nof

peroxiredo

xins

and

mito

chon

drialstructuralgenes

norm

alizationin

mito

chon

drianu

mber

[200]

Mito

QMethanesulfo

nate

Invivo

APP

transgenicmice

Maintenance

ofmito

chon


n:Cy

pDexpressio

n

Invivo

3xTg

-ADmice

Maintenance

ofmito

chon


n:preventio

nof

MMPloss

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

blockage

ofcaspases-3/7

activ

ation

[171]

Invivo

Caenorhabditiseleg

ansm

odeloverexpressin

ghu

man

A

peptides

Maintenance

ofmito

chon


n,depletionof

mito

chon

driallipid

cardiolip

inProtectio

nof

complexes

IVandIo

fthe

ETC

[201]


Table2:Con

tinued.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

Mito

chon

drial

divisio

ninhibitor1

(Mdivi-1)

Quinazolin

one

Invitro

A-in

ducedmou

seBV

-2cells

andprim

arymicroglial

cells

mod

el

Maintenance

ofmito

chon


n:abno

rmalmito

chon

drialfi

ssion

MMPloss

Cy

tCrelease

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-3activ

ation

[182]

Invitro

cybrid

cells

mod

el(m

tDNA-depleted

neuron

alSH

5Y5Y

cells

transfe

cted

with

plateletmito

chon

driafro

mADpatient)

Maintenance

ofmito

chon


n:mito

chon

drialR

OSprod

uctio

nMMP

mito

chon

driallengthanddensity

Cy

tCoxidasea

ctivity

SO

Dactiv

ityAT

Plevels

im

paire

dmito

chon

drialfi

ssionandfusio

ndynamics

[174]

N-Acetylcysteine

Aminoacid

deriv

ative

Invitro-amyloid-indu

cedhu

man

HCN

-1Acells

mod

elMaintenance

ofmito

chon


n:mito

chon

drialm

embraned

epolarization

[193]

Invivo

APP

/PS-1m

ice

Ameliorationof

energy

levelsandmito

chon

drial-related

proteins

[202]

Invitro

fibroblastsfro

mADpatients

Maintenance

ofmito

chon


n:NMP-indu

cedmito

chon

drialoxidativ

estre

ssInhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

xandcaspase-9levels

[196]

Neuregulin

-1Peptide

Invitro

mod

elof

SH-SY5

Yhu

man

neurob

lasto

mac

ells

transfe

cted

with

C-term

inalfragmentsof

APP

Maintenance

ofmito

chon


n:MMPloss

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2expressio

n

[203]

Nicotinam

ide

Amide

Invivo

A142-in

ducedratm

odel

Upregulationof

mito

chon

drialfun

ction

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2levels

Ba

xlevels

[204]

Peroxiredo

xin3

Enzyme

Invivo

APP

transgenicmice(Tg

2576)and

APP

/Prdx3

transgenicmicem

odels

Maintenance

ofmito

chon


n:mito

chon

drialD

NAoxidation

activ

ityof

mito

chon

drialcom

plexes

Iand

IV[205]

Peroxiredo

xin6

Enzyme

Invitro

A2535-in

ducedPC

12cells

mod

el

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspases

3and9activ

ation

PA

RPactiv

ation

Bc

l-2andBa

xdysregulations

[206]


Table2:Con

tinued.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

Probucol

In

vitro

cybrid

cells

mod

el(m

tDNA-depleted

neuron

alSH

5Y5Y

cells

transfe

cted

with

plateletmito

chon

driafro

mADpatient)

Maintenance

ofmito

chon


n:mito

chon

drialR

OSprod

uctio

nMMP

mito

chon

driallengthanddensity

Cy

tCoxidasea

ctivity

SO

Dactiv

ityAT

Plevels

im

paire

dmito

chon

drialfi

ssionandfusio

ndynamics

[174]

Puerarin

Phytoestrogen

Invivo

A142-in

ducedratm

odel

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspase-9activ

ityandmRN

Alevels

[207]

Invitro

cybridcells

mod

el(m

tDNA-depleted

neuron

alSH

-5Y5

Ycells

transfe

cted

with

plateletmito

chon

driafro

mADpatient)

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Bc

l-2levels

Ba

xexpressio

ncaspase-3activ

ity

[208]

R(+)

andS()

pram

ipexoles

In

vitro

A2535-in

ducedSH

-SY5

Yhu

man

neuroblasto

mac

ells

mod

el

Maintenance

ofmito

chon


n:inhibitio

nof

mPT

Pop

ening

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

caspases

3and9activ

ations

[209]

Resistin

Adipokinep

rotein

Invitro

mou

seN2a/Swe.

9cells

(N2a

cells

transfe

cted

with

Sw-APP

mutantand

presenilinexon

9deletio

nmutant)

Maintenance

ofmito

chon


n:AT

Plevels

MMP

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

Ba

x/Bc

l2ratio

Cy

tCrelease

caspase-3activ

ation

[210]

Resveratrol

Polyph

enol

Invitro

A-in

ducedmou

seneurob

lasto

maN

2acells

mod

el

Maintenance

ofmito

chon


n:abno

rmalexpressio

nof

peroxiredo

xins

and

mito

chon


Normalizationin

mito

chon

drianu

mber

[200]

Invivo

APP

transgenicmice

Maintenance

ofmito

chon


n:Cy

pDexpressio

nSalicylate

Sulin

dacs

ulfid

eIndo

methacin

Ibup

rofen

R-flu

rbiprofen

NSA

IDs

Invitro

A142-a

ndA2535-in

ducedratcerebellarg

ranu

lecells

andcorticalneuron

smod

el

Maintenance

ofmito

chon


n:MMP

mito

chon

drialC

a2+overload

Cy

tCrelease

[172]

20 Oxidative Medicine and Cellular LongevityTa

ble2:Con

tinued.

Com

poun

dClasso

fcom

poun

dADmod

elMechanism

/effect

References

SS31

Peptide

Invitro

A2535-in

ducedC5

7BL/6miceh

ippo

campaln

eurons

mod

el

Maintenance

ofmito

chon


n:levelsof

mito

chon

drialfi

ssionproteins

(Drp1,

Fis1),matrix

protein,andCy

pDnu

mbero

fhealth

yandintactmito

chon

dria

Resto

ratio

nof

mito

chon

drialtranspo

rt

[162]

Invitro

A-in

ducedmou

seneurob

lasto

maN

2acells

mod

el

Maintenance

ofmito

chon


n:abno

rmalexpressio

nof

peroxiredo

xins

and

mito

chon


Normalizationin

mito

chon

drianu

mber

[200]

Invivo

APP

transgenicmice

Maintenance

ofmito

chon


n:Cy

pDexpressio

n

Invitro

Tg2576

micep

rimaryneuron

sMaintenance

ofmito

chon


n:resto

ratio

nof

mito

chon

drialtranspo

rtpercentage

ofdefectivem

itochon

dria

[211]

Thym

oquino

neBe

nzoq

uino

neIn

vitro

A2535-in

ducedPC

12cells

mod

elMaintenance

ofmito

chon


n:MMP

[212]

Invitro

A142-in

ducedprim

aryratn

eurons

mod

elMaintenance

ofmito

chon


n:MMP

[213]

Tournefolic

acid

BPo

lyph

enol

Invitro2535-in

ducedratcorticalneuron

smod

el

Maintenance

ofmito

chon


n:mito

chon

drialC

a2+levels

delay

inCy

tCrelease

Inhibitio

nof

them

itochon

drialapo

ptoticpathway:

tBid

levels

[214]

Trolox

Analogof

vitamin

EIn

vitro

dentateg

ranu

lecells

from

transgenicmou

seADmod

el(Tg2576)

Maintenance

ofmito

chon


n:scavenging

ofmito

chon

drialSO

resto

ratio

nof

Ca2+cle

arance

MMP

[215]

UPF

1and

UPF

17Peptides

Mito

chon

drialfractionof

postm

ortem

human

ADbrains

Mito

chon

drialM

n-SO

Dactiv

ity[191]

Vitamin

CVitamin

Invitro

A-in

ducedhu

man

HCN

-1Acells

mod

elMaintenance

ofmito

chon


n:mito

chon

drialm

embraned

epolarization

[193]

Invivo

5XFA

DKn

ockout-tr

ansgenicmicem

odel

Maintenance

ofmito

chon


n:preventio

nof

abno

rmalmito

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