Loss of functional
            <scp>OPA</scp>
            1 unbalances redox state: implications in dominant optic atrophy pathogenesis

Millet, Aurélie; Bertholet, Ambre M.; Daloyau, Marlène; Reynier, Pascal; Galinier, Anne; Devin, Anne; Wissinguer, Bernd; Bélenguer, Pascale; Davezac, Noélie

doi:10.1002/acn3.305

Cited by 34 publications

(62 citation statements)

References 68 publications

(88 reference statements)

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“…B). These findings resemble those previously reported in fibroblasts from a patient carrying the same I382M mutation . Moreover, the deleterious score of the I382M mutation reinforces the pathogenic character of this variant (Table ).…”

Section: Resultsmentioning

confidence: 99%

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Kane

Alban

Desquiret-Dumas

et al. 2017

J Cellular Molecular Medi

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Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype-phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant-negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.

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Section: Resultsmentioning

confidence: 99%

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Kane

Alban

Desquiret-Dumas

et al. 2017

J Cellular Molecular Medi

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“…For example, drp-1 -, fzo-1 ( MFN2 homolog)-, and eat-3 ( OPA1 homolog)-deficient C. elegans are sensitive to rotenone-induced lethality (Fig. 2) and larval growth delay ( fzo-1 & eat-3 only: (Luz et al 2017)); rotenone reduces the viability of cortical neurons isolated from heterozygous OPA1 +/− rats (Millet et al 2016); and transfection with OPA1 G300E , an OPA1 variant carrying a missense mutation in the GTPase domain, sensitizes primary mice neurons to rotenone-induced axonal degeneration (Lassus et al 2016). Furthermore, mutations in drp-1 have been reported to mildly sensitize nematodes to paraquat-induced lethality and larval growth delay (Luz et al 2017; Yang et al 2011) while fusion-deficient C. elegans ( eat-3, fzo-1 ) are sensitive to paraquat-induced lethality and larval growth delay, and D. melanogaster ( OPA1 -deficient) display reduced survival following paraquat exposure (Kanazawa et al 2008; Luz et al 2017; Tang et al 2009).…”

Section: Gene-environment Interactions: How Does Genetic Variationmentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.

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“…; Millet et al . ). This was associated with a reduction of synapse quantity and a dendropathy, both being observed in vivo in RGC on a DOA mouse model (Williams et al .…”

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confidence: 97%

OPA1 haploinsufficiency induces a BNIP3‐dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy

Moulis

Millet

Daloyau

et al. 2016

Journal of Neurochemistry

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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.

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Loss of functional OPA 1 unbalances redox state: implications in dominant optic atrophy pathogenesis

Cited by 34 publications

References 68 publications

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Mitochondrial fusion, fission, and mitochondrial toxicity

OPA1 haploinsufficiency induces a BNIP3‐dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy

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