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OPA1 haploinsufficiency induces a BNIP3‐dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy
Author(s) -
Moulis Ma F,
Millet Aurélie M,
Daloyau Marlène,
Miquel MarieChristine,
Ronsin Brice,
Wissinger Bernd,
ArnaunéPelloquin Laetitia,
Belenguer Pascale
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13894
Subject(s) - mitophagy , autophagy , pathogenesis , biology , microbiology and biotechnology , haploinsufficiency , atrophy , mitochondrion , apoptosis , neuroscience , in vivo , programmed cell death , phenotype , genetics , immunology , gene
Dominant optic atrophy (DOA) is because of mutations in the mitochondrial protein OPA1. The disease principally affects retinal ganglion cells, whose axons degenerate leading to vision impairments, and sometimes other neuronal phenotypes. The exact mechanisms underlying DOA pathogenesis are not known. We previously demonstrated that the main role of OPA1, as a mitochondrial fusogenic and anti‐apoptotic protein, are inhibited by interaction with the stress inducible pro‐apoptotic BNIP3 protein. Because BNIP3 was recently reported to participate in autophagy and mitophagy, we tested the involvement of these processes in DOA pathogenesis. Using an in vitro neuronal model of DOA, we identified a BNIP3 down‐regulation that reduced autophagy and mitophagy. Restoring BNIP3 had a biphasic effect, first rescuing autophagy and mitophagy levels but later leading to cell death. Similarly, in an in vivo mouse model of DOA, we showed that BNIP3 levels are decreased in young adult mice and increase to normal levels upon aging, paralleling disease progression. Altogether, our results indicate that the relationship between OPA1 and BNIP3 may have important bearings on DOA pathogenesis.