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The genetic pathophysiology of dominant optic atrophy
Author(s) -
Lenaers G.,
Charif M.,
AmatiBonneau P.,
Chao de la Barca J.,
Procaccio V.,
Gerber S.,
Kaplan J.,
Roubertie A.,
Meunier I.,
Reynier P.,
Rozet J.M.,
Hamel C.,
Bonneau D.
Publication year - 2016
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2016.0117
Subject(s) - mitochondrial fusion , biology , optic nerve , mitochondrial dna , mitochondrion , atrophy , optic neuropathy , retinal ganglion cell , mitochondrial fission , gene , genetics , axoplasmic transport , mitochondrial disease , neuroscience , microbiology and biotechnology
Summary Inherited Optic Neuropathies are blinding diseases related to mitochondrial dysfunctions jeopardizing retinal ganglion cell (RGC) survival. There are two main forms: the Leber Hereditary Optic Neuropathy (LHON) related to mutations in the mitochondrial genome, and the Kjer dominant optic atrophy (DOA) related to mutations in nuclear genes. Since the initial discovery of the OPA1 gene in 2000 as the major gene causing DOA, the use of WES and re‐sequencing chips disclosed many novel genes responsible for DOA. Interestingly, most of them are involved in mitochondrial dynamics, suggesting that the equilibrium between fission and fusion is crucial for RGC physiology. In this respect, using fluorescence and electron microscopy, we showed that the structure of mitochondria is drastically different according to the myelination status of RGC axons, possibly correlating anterograde and retrograde mitochondrial transport to mitochondrial dynamics. Further metabolomics analysis of an Opa1 mouse model identified specific signatures in the plasma and optic nerve, emphasizing the consequence of mitochondrial shape on metabolic pathways, and revealing biomarkers of the disease.