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J. Biol. Chem., Vol. 279, Issue 18, 18792-18798, April 30, 2004

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Loss of the Intermembrane Space Protein Mgm1/OPA1 Induces Swelling and Localized Constrictions along the Lengths of Mitochondria^*

Lorena Griparic, Nicole N. van der Wel¶, Ian J. Orozco, Peter J. Peters¶, and Alexander M. van der Bliek||

From the Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California and the ^¶Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Mgm1 is a member of the dynamin family of GTP-binding proteins. Mgm1 was first identified in yeast, where it affects mitochondrial morphology. The human homologue of Mgm1 is called OPA1. Mutations in the OPA1 gene are the prevailing cause of dominant optic atrophy, a hereditary disease in which progressive degeneration of the optic nerve can lead to blindness. Here we investigate the properties of the Mgm1/OPA1 protein in mammalian cells. We find that Mgm1/OPA1 is localized to the mitochondrial intermembrane space, where it is tightly bound to the outer surface of the inner membrane. Overexpression of wild type or mutant forms of the Mgm1/OPA1 protein cause mitochondria to fragment and, in some cases, cluster near the nucleus, whereas the loss of protein caused by small interfering RNA (siRNA) leads to dispersal of mitochondrial fragments throughout the cytosol. The cristae of these fragmented mitochondria are disorganized. At early time points after transfection with Mgm1/OPA1 siRNA, the mitochondria are not yet fragmented. Instead, the mitochondria swell and stretch, after which they form localized constrictions similar to the mitochondrial abnormalities observed during the early stages of apoptosis. These abnormalities might be the earliest effects of losing Mgm1/OPA1 protein.

Received for publication, January 28, 2004

^* This work was supported in part by American Cancer Society Grant RSG-01-147-01-CSM), National Institutes of Health Grant GM051866, and a grant from the Cancer Research Coordinating Committee (to A. v. d. B.). 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.

Supported by a fellowship from the American Heart Association Western States Affiliates.

^|| To whom correspondence should be addressed: Dept. of Biological Chemistry 33-257 CHS, David Geffen School of Medicine at UCLA, P. O. Box 951737, Los Angeles, CA 90095. Tel.: 310-825-9779; Fax: 310-206-5272; E-mail: avan{at}mednet.ucla.edu.

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