In:
Journal of Cellular and Molecular Medicine, Wiley, Vol. 21, No. 10 ( 2017-10), p. 2284-2297
Abstract:
Optic Atrophy 1 ( OPA 1) gene mutations cause diseases ranging from isolated dominant optic atrophy ( DOA ) to various multisystemic disorders. OPA 1, a large GTP ase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA 1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA 1 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 OPA 1 mutations. We report new genotype–phenotype correlations between various types of OPA 1 mutation and mitophagy. Fibroblasts bearing dominant‐negative OPA 1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA 1 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 OPA 1 mutations, suggesting that the level and profile of OPA 1 may regulate the rate of mitophagy.
Type of Medium:
Online Resource
ISSN:
1582-1838
,
1582-4934
DOI:
10.1111/jcmm.2017.21.issue-10
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2076114-4
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