title: Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.
abstract: Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.
authors.affiliation: Adolf-Butenandt-Institut für Physiologische Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5, 81377 München, Germany.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Duvezin-Caubet
authors.forename: Ravi
authors.initials: R
authors.lastname: Jagasia
authors.forename: Johannes
authors.initials: J
authors.lastname: Wagener
authors.forename: Sabine
authors.initials: S
authors.lastname: Hofmann
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
authors.forename: Anna
authors.initials: A
authors.lastname: Hansson
authors.forename: Anne
authors.initials: A
authors.lastname: Chomyn
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Bauer
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Attardi
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.forename: Walter
authors.initials: W
authors.lastname: Neupert
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Reichert
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004734:Energy Metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D011499:Protein Processing, Post-Translational
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D007527:Isoenzymes; C081930:Tfam protein, mouse; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C498809:Opa1 protein, mouse