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OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion
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OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion
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Journal Article
OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion
2023
Overview
Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.
Publisher
National Academy of Sciences
Subject
/ Cristae
/ GTP Phosphohydrolases - genetics
/ GTP Phosphohydrolases - metabolism
/ Humans
/ Mitochondrial Membranes - metabolism
/ Mutants
/ Mutation
/ Optic Atrophy, Autosomal Dominant - genetics
/ Optic Atrophy, Autosomal Dominant - metabolism
/ Optic Atrophy, Autosomal Dominant - pathology
/ Proteins
/ Splicing
