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.

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

“…This is in agreement with recent reports documenting the alteration of mitophagic and autophagic activities in OPA1-related diseases [12,47]. Studies on in vitro neuronal models and an in vivo mouse model of OPA1 insufficiency have shown that the down-regulation of OPA1 reduces the level of BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) [47], previously implicated in the induction of mitophagy and autophagy [48]. While the reduction of mitophagy and autophagy is not itself sufficient to induce spontaneous apoptotic cell death, it contributes greatly to the susceptibility of neurons to chronic and acute stress [28].…”

“…We hypothesize that the reduction of autophagy and mitophagy, particularly the absence of stimulation of these pathways, may be part of the pathophysiology of OPA1 mutations leading to haploinsufficiency. This is in agreement with recent reports documenting the alteration of mitophagic and autophagic activities in OPA1-related diseases [12,47]. Studies on in vitro neuronal models and an in vivo mouse model of OPA1 insufficiency have shown that the down-regulation of OPA1 reduces the level of BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) [47], previously implicated in the induction of mitophagy and autophagy [48].…”

Targeted OMA1 therapies for cancer

“…in vitro experiments revealed an interaction of OPA1 with BNIP3’s carboxyl‐terminus in a phosphorylation‐dependent manner, which led to disassembly of OPA1 complexes and prompted cytochrome c release . Interestingly, cortical neurons showed a correlation of BNIP3 levels and disease progression in mutant OPA1 mice providing further support for a functional connection between OPA1 and BNIP3 . OPA1 was also identified as parkin interaction partner in proteomics studies combining tandem affinity purification and mass spectrometry profiling .…”

“…[98][99][100][101] Interestingly, cortical neurons showed a correlation of BNIP3 levels and disease progression in mutant OPA1 mice providing further support for a functional connection between OPA1 and BNIP3. 102 OPA1 was also identified as parkin interaction partner in proteomics studies combining tandem affinity purification and mass spectrometry profiling. 103 The parkin E3 ubiquitin protein ligase is part of an ubiquitin ligase complex recruited to the mitochondrial outer membrane upon loss of the membrane potential Δψ.…”

Validating the RedMIT/GFP-LC3 Mouse Model by Studying Mitophagy in Autosomal Dominant Optic Atrophy Due to the OPA1Q285STOP Mutation

“…Thirdly, it is possible that mitophagy is not actually increased in RGCs in OPA1 knock down. Indeed, Belenguer showed that BNIP3 dependent mitophagy is actually decreased in a neuronal model of OPA1 knock-down (Moulis et al, 2017 ). Given that we previously showed that mitophagy declines with maturity in fibroblasts (Diot et al, 2015 ), we suggest that their neuronal cultures may not reflect in vivo mature RGCs.…”