Calpain 10: A mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction

David D. Arrington, Terry R. Van Vleet, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

Calpains, Ca2+-activated cysteine proteases, are cytosolic enzymes implicated in numerous cellular functions and pathologies. We identified a mitochondrial Ca2+-inducible protease that hydrolyzed a calpain substrate (SLLVY-AMC) and was inhibited by active site-directed calpain inhibitors as calpain 10, an atypical calpain lacking domain IV. Immunoblot analysis and activity assays revealed calpain 10 in the mitochondrial outer membrane, intermembrane space, inner membrane, and matrix fractions. Mitochondrial staining was observed when COOH-terminal green fluorescent protein-tagged calpain 10 was overexpressed in NIH-3T3 cells and the mitochondrial targeting sequence was localized to the NH2-terminal 15 amino acids. Overexpression of mitochondrial calpain 10 resulted in mitochondrial swelling and autophagy that was blocked by the mitochondrial permeability transition (MPT) inhibitor cyclosporine A. With the use of isolated mitochondria, Ca2+-induced MPT was partially decreased by calpain inhibitors. More importantly, Ca2+-induced inhibition of Complex I of the electron transport chain was blocked by calpain inhibitors and two Complex I proteins were identified as targets of mitochondrial calpain 10, NDUFV2, and ND6. In conclusion, calpain 10 is the first reported mitochondrially targeted calpain and is a mediator of mitochondrial dysfunction through the cleavage of Complex I subunits and activation of MPT.

Original languageEnglish (US)
Pages (from-to)C1159-C1171
JournalAmerican Journal of Physiology - Cell Physiology
Volume291
Issue number6
DOIs
StatePublished - Dec 2006
Externally publishedYes

Keywords

  • Protease
  • Respiration

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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