title: The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure.
abstract: The protein optic atrophy 1 (OPA1) is a dynamin-related protein associated with the inner mitochondrial membrane and functions in mitochondrial inner membrane fusion and cristae maintenance. Inner membrane-anchored long OPA1 (L-OPA1) undergoes proteolytic cleavage resulting in short OPA1 (S-OPA1). It is often thought that S-OPA1 is a functionally insignificant proteolytic product of L-OPA1 because the accumulation of S-OPA1 due to L-OPA1 cleavage is observed in mitochondrial fragmentation and dysfunction. However, cells contain a mixture of both L- and S-OPA1 in normal conditions, suggesting the functional significance of maintaining both OPA1 forms, but the differential roles of L- and S-OPA1 in mitochondrial fusion and energetics are ill-defined. Here, we examined mitochondrial fusion and energetic activities in cells possessing L-OPA1 alone, S-OPA1 alone, or both L- and S-OPA1. Using a mitochondrial fusion assay, we established that L-OPA1 confers fusion competence, whereas S-OPA1 does not. Remarkably, we found that S-OPA1 alone without L-OPA1 can maintain oxidative phosphorylation function as judged by growth in oxidative phosphorylation-requiring media, respiration measurements, and levels of the respiratory complexes. Most strikingly, S-OPA1 alone maintained normal mitochondrial cristae structure, which has been commonly assumed to be the function of OPA1 oligomers containing both L- and S-OPA1. Furthermore, we found that the GTPase activity of OPA1 is critical for maintaining cristae tightness and thus energetic competency. Our results demonstrate that, contrary to conventional notion, S-OPA1 is fully competent for maintaining mitochondrial energetics and cristae structure.
authors.affiliation: From the Departments of Physiology and.
authors.forename: Hakjoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: From the Departments of Physiology and yyoon@augusta.edu.
authors.forename: Yisang
authors.initials: Y
authors.lastname: Yoon
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D004272:DNA, Mitochondrial / Q000378:metabolism; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D059748:Proteolysis
chemical_list: D004272:DNA, Mitochondrial; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C498809:Opa1 protein, mouse; D010100:Oxygen
keywords: OPA1; bioenergetics; cristae; mitochondria; mitochondrial disease; mitochondrial fusion; mitochondrial metabolism; mitochondrial respiratory chain complex