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Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization

Möpert, Kristin and Hajek, Petr and Frank, Stephan and Chen, Christiane and Kaufmann, Jörg and Santel, Ansgar (2009) Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization. Experimental Cell Research, 315 (13). pp. 2165-2180. ISSN 0014-4827.

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RNAi mediated loss of Drp1 function changes mitochondrial morphology in cultured HeLa and HUVEC cells by shifting the balance of mitochondrial fission and fusion towards unopposed fusion. Over time, inhibition of Drp1 expression results in the formation of a highly branched mitochondrial network along with “bulge”-like structures. These changes in mitochondrial morphology are accompanied by a reduction in levels of Mitofusin 1 (Mfn1) and 2 (Mfn2) and a modified proteolytic processing of OPA1 isoforms, resulting in the inhibition of cell proliferation. In addition, our data imply that bulge formation is driven by Mfn1 action along with particular proteolytic short-OPA1 (s-OPA1) variants: Loss of Mfn2 in the absence of Drp1 results in an increase of Mfn1 levels along with processed s-OPA1-isoforms, thereby enhancing continuous “fusion” and bulge formation. Moreover, bulge formation might reflect s-OPA1 mitochondrial membrane remodeling activity, resulting in the compartmentalization of cytochrome c deposits. The proteins Yme1L and PHB2 appeared not associated with the observed enhanced OPA1 proteolysis upon RNAi of Drp1, suggesting the existence of other OPA1 processing controlling proteins. Taken together, Drp1 appears to affect the activity of the mitochondrial fusion machinery by unbalancing the protein levels of mitofusins and OPA1.

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Additional Information:Copyright © 2009 Elsevier. Received 8 December 2008; revised 10 April 2009; accepted 23 April 2009. Available online 4 May 2009. We are grateful to Oliver Keil and Jens Endruschat (both Silence Therapeutics AG) for providing us with AtuFECT01, Frank Gebhardt and Ralf Sägebarth for siRNA design. We thank A. van der Bliek for sharing plasmids. Joy Hatzidakis is greatly acknowledged for critical reading of the manuscript. Klaus Giese is acknowledged for support of this research. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.yexcr.2009.04.016.
Subject Keywords:RNAi; Mitofusin; Proliferation; Prohibitin; Yme1L; Inner-mitochondrial membrane
Issue or Number:13
Record Number:CaltechAUTHORS:20090910-130956548
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Official Citation:Kristin Mopert, Petr Hajek, Stephan Frank, Christiane Chen, Jorg Kaufmann, Ansgar Santel, Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization, Experimental Cell Research, Volume 315, Issue 13, 1 August 2009, Pages 2165-2180, ISSN 0014-4827, DOI: 10.1016/j.yexcr.2009.04.016. (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15731
Deposited By: George Porter
Deposited On:07 Oct 2009 18:02
Last Modified:03 Oct 2019 01:02

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