Expanding the ocular involvement in mitochondrial disorders

Prof. Valerio Carelli

Laboratorio di Neurogenetica

IRCCS Institute of Neurological Sciences of Bologna,Bellaria Hospital, Bologna, ItalyNeurology Unit, Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy

Leber Hereditary Optic Neuropathy (mtDNA)

Dominant optic atrophy (OPA1)Recessive optic atrophyX-linked optic atrophy

Mitochondrial “Fission/Fusion”: new phenotypes with old and new genes

DOA “plus”In 2008 we reported eight patients from sixindependent families showing thatmutations in the OPA1 gene can also beresponsible for a syndromic form of DOAcharacterized by:

• optic atrophy• sensorineural deafness• ataxia• axonal sensory-motor polyneuropathy• chronic progressive external ophthalmoplegia - CPEO • mitochondrial myopathy with mtDNA multiple deletions

Old genes, new phenotypes 1: OPA1 – CPEO, neurodegeneration (parkinsonism and

dementia) and mtDNA multiple deletions

mtDNA multiple deletions in skeletal muscle

Increased basal autophagy in fibroblastsand increased fragmentation (fusion defect)

Abnormal mitophagy in OPA1 mutant fibroblasts

PARIS NEMO

EXPLORING the Pink1/Parkin/OPA1 connection

OPAthies

Parkinsonism/Dementia

DOA, DOA “plus”/CPEO - mtDNA multiple deletions

Old genes, new phenotypes 2: AFG3L2/SCA28 – assembles with the paralogous Paraplegin protein (SPG7) to form the oligomeric mAAA protease complex involved in mitochondrial protein maturation and degradation - implicated in OPA1 processing

Family 1 (Puglia – DOA)

Family 2 (Campania – DOA)

Two large Italian families with the same mutation in AFG3L2/SCA28 (exon 11, c.1385C>T, p.Arg462Val, unpublished results)

Isolated dominant optic neuropathy (DOA)with heterozygous novel SPG7 missensemutation c.1232A>C (p.Asp411Ala)

DOA, DOA “plus”/CPEO - mtDNA multiple deletions

DOA, CPEOmtDNA multiple deletions

DOA, CPEOmtDNA multiple deletions

DOA and mtDNA multiple deletions

New genes 1: SLC25A46 – a modified carrier protein recruited to the outer mitochondrial membrane, an UGO1-like protein

Loss of function unexpectedly leads to increased mitochondrial connectivity

Patient derived fibroblasts confirm the silencing experiments

New genes 2: RTN4 Interacting Protein 1 – RTN4IP1a mitochondrial (outer membrane) ubiquinol

oxydo-reductase partner of RTN4 (NOGO), an ER protein involved in dendritogenesis/branching and

susceptibility to UV light

Silencing of RTN4IP1 induced altered number and morphogenesis of mouse RGC dendrites

Loss of the altered protein and deficit of complex I and IV activities

PANNELLO DI 36 GENI PER ATROFIE OTTICHE EREDITARIE

UOC CLINICA NEUROLOGICA, IRCCS ISTITUTO DELLE SCIENZE NEUROLOGICHE DI BOLOGNA, LABORATORIO DI NEUROBIOLOGIA, OSPEDALE BELLARIA, BOLOGNA

ESPERIENZA RECENTE CON IL PANNELLO DIAGNOSTICO PER LE ATROFIE OTTICHE

Nuclear allotopic expression of a mitochondrial recoded gene (ND4) targeted to mitochondria

Thanks for your attention and to the many collaborators:• Alfredo A. Sadun, USC, Los Angeles• Rubens Belfort Jr, UNIFESP, Sao Paolo• Carla Giordano, University “La Sapienza”, Rome• Palmiro Cantatore, University of Bari, Bari• Anna Ghelli, University of Bologna, Bologna• Pio D’Adamo, University of Trieste, Trieste• Vamsi Mootha, Harvard, Boston• Massimo Zeviani, MRC, Cambridge• Patrick Chinnery and Patrick Yu-Wai-Man, • University of Newcastle, Newcastle• Piero Barboni, San Raffaele, Milano

• ………and my lab: