CaltechAUTHORS
  A Caltech Library Service

Proteolytic Processing of OPA1 Links Mitochondrial Dysfunction to Alterations in Mitochondrial Morphology

Duvezin-Caubet, Stéphane and Jagasia, Ravi and Wagener, Johannes and Hofmann, Sabine and Trifunovic, Aleksandra and Hansson, Anna and Chomyn, Anne and Bauer, Matthis F. and Attardi, Giuseppe and Larsson, Nils-Göran and Neupert, Walter and Reichert, Andrea S. (2006) Proteolytic Processing of OPA1 Links Mitochondrial Dysfunction to Alterations in Mitochondrial Morphology. Journal of Biological Chemistry, 281 (49). pp. 37972-37979. ISSN 0021-9258. https://resolver.caltech.edu/CaltechAUTHORS:DUVjbc06

[img]
Preview
PDF - Published Version
See Usage Policy.

914Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:DUVjbc06

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1074/jbc.M606059200DOIUNSPECIFIED
Additional Information:© 2006 American Society for Biochemistry and Molecular Biology. Received for publication, June 26, 2006, and in revised form, September 1, 2006 Published, JBC Papers in Press, September 26, 2006, DOI 10.1074/jbc.M606059200 We thank Drs. Luca Scorrano and Heidi McBride for plasmids, Prof. Antonio Zorzano for antibodies, Iris Haag for technical assistance, and Drs. Juan Alfonzo and Doron Rapaport for comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft/SFB 594-B8 (to A. S. R.), NGFN I/MITOP (to A. S. R. and W. N.), the Friedrich-Baur-Stiftung (to A. S. R.), the Alexander von Humboldt Foundation (to R. J.), the LMU München/FöFoLe (to J. W.), and the National Institutes of Health Grant GM11726 (to A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)SFB 594-B8
Friedrich-Baur-StiftungUNSPECIFIED
Alexander von Humboldt FoundationUNSPECIFIED
LMU München/FöFoLeUNSPECIFIED
NIHGM11726
Issue or Number:49
Record Number:CaltechAUTHORS:DUVjbc06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:DUVjbc06
Official Citation:Stéphane Duvezin-Caubet, Ravi Jagasia, Johannes Wagener, Sabine Hofmann, Aleksandra Trifunovic, Anna Hansson, Anne Chomyn, Matthias F. Bauer, Giuseppe Attardi, Nils-Göran Larsson, Walter Neupert, and Andreas S. Reichert Proteolytic Processing of OPA1 Links Mitochondrial Dysfunction to Alterations in Mitochondrial Morphology J. Biol. Chem. 2006 281: 37972-. doi:10.1074/jbc.M606059200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6808
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:23 Dec 2006
Last Modified:02 Oct 2019 23:36

Repository Staff Only: item control page