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Vol. 18, Issue 9, 3582-3590, September 2007
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*Institute for Physiological Chemistry, Ludwig Maximilians University, 81377 Munich, Germany; Institute for Genetics and Center for Molecular Medicine, University of Cologne, D-50674 Cologne, Germany; Protein Analysis Unit, Ludwig Maximilians University, 80336 Munich, Germany; ||Division of Biochemistry and Genetics, National Neurological Institute, 20133 Milan, Italy; ¶Institute of Developmental Genetics, Forschungszentrum für Umwelt und Gesundheit–National Research Center for Environment and Health, 85764 Munich-Neuherberg, Germany; and #Department of Neuroscience and Medical Biotechnologies, University of Milano-Bicocca, 20126 Milan, Italy
Submitted February 22, 2007;
Revised June 13, 2007;
Accepted June 21, 2007
Monitoring Editor: Janet Shaw
The morphology of mitochondria in mammalian cells is regulated by proteolytic cleavage of OPA1, a dynamin-like GTPase of the mitochondrial inner membrane. The mitochondrial rhomboid protease PARL, and paraplegin, a subunit of the ATP-dependent m-AAA protease, were proposed to be involved in this process. Here, we characterized individual OPA1 isoforms by mass spectrometry, and we reconstituted their processing in yeast to identify proteases involved in OPA1 cleavage. The yeast homologue of OPA1, Mgm1, was processed both by PARL and its yeast homologue Pcp1. Neither of these rhomboid proteases cleaved OPA1. The formation of small OPA1 isoforms was impaired in yeast cells lacking the m-AAA protease subunits Yta10 and Yta12 and was restored upon expression of murine or human m-AAA proteases. OPA1 processing depended on the subunit composition of mammalian m-AAA proteases. Homo-oligomeric m-AAA protease complexes composed of murine Afg3l1, Afg3l2, or human AFG3L2 subunits cleaved OPA1 with higher efficiency than paraplegin-containing m-AAA proteases. OPA1 processing proceeded normally in murine cell lines lacking paraplegin or PARL. Our results provide evidence for different substrate specificities of m-AAA proteases composed of different subunits and reveal a striking evolutionary switch of proteases involved in the proteolytic processing of dynamin-like GTPases in mitochondria.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
These authors contributed equally to this work.
Address correspondence to: Andreas S. Reichert (andreas.reichert{at}med.uni-muenchen.de) or Thomas Langer (thomas.langer{at}uni-koeln.de).
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