The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking

Authors

  • Cathrin Meissner,

    1. Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
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  • Holger Lorenz,

    1. Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
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  • Andreas Weihofen,

    1. Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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    • The present address of Andreas Weihofen is the Neurimmune Therapeutics AG, 8952 Schlieren, Switzerland.

  • Dennis J. Selkoe,

    1. Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • Marius K. Lemberg

    1. Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
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  • Following submission of our paper, Jin et al. (2010) and Deas et al. independently published results that are consistent with those described herein.

Address correspondence and reprint requests to Marius K. Lemberg, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. E-mail: m.lemberg@zmbh.uni-heidelberg.de

Abstract

J. Neurochem. (2011) 117, 856–867.

Abstract

Intramembrane proteolysis is a conserved mechanism that regulates a variety of cellular processes ranging from transcription control to signaling. In mitochondria, the inner membrane rhomboid protease PARL has been implicated in the control of life span and apoptosis by a so far uncharacterized mechanism. Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson’s disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. As targeting of this precursor to the outer mitochondrial membrane has been shown to trigger mitophagy, we suggest that the PARL-catalyzed removal of the Pink1 signal sequence in the canonical import pathway acts as a cellular checkpoint for mitochondrial integrity. Furthermore, we show that two Parkinson’s disease-causing mutations decrease the processing of Pink1 by PARL, with attendant implications for pathogenesis.

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