title: OPA1 haploinsufficiency induces a BNIP3-dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy.
abstract: 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.
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Manon F
authors.initials: MF
authors.lastname: Moulis
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Aurélie M
authors.initials: AM
authors.lastname: Millet
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Daloyau
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Miquel
authors.affiliation: Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Ronsin
authors.affiliation: Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Arnauné-Pelloquin
authors.affiliation: Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Belenguer
mesh_terms: D000818:Animals; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D057895:Haploinsufficiency / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
chemical_list: C508686:BNip3 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse
keywords: BNIP3; OPA1; dominant optic atrophy; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases