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Duvezin-Caubet, S.* ; Jagasia, R. ; Wagener, J.* ; Hofmann, S.* ; Trifunovic, A.* ; Hansson, A.* ; Chomyn, A.* ; Bauer, M.F.* ; Attardi, G.* ; Larsson, N.G.* ; Neupert, W.* ; Reichert, A.S.*

Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.

J. Biol. Chem. 281, 37972 (2006)
DOI
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Journal Journal of Biological Chemistry, The
Quellenangaben Volume: 281, Issue: 49, Pages: 37972 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)