Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death

Denis Martinvalet, Derek M. Dykxhoorn, Roger Ferrini, Judy Lieberman

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

The killer lymphocyte protease granzyme A (GzmA) triggers caspase-independent target cell death with morphological features of apoptosis. We previously showed that GzmA acts directly on mitochondria to generate reactive oxygen species (ROS) and disrupt the transmembrane potential (ΔΨm) but does not permeabilize the mitochondrial outer membrane. Mitochondrial damage is critical to GzmA-induced cell death since cells treated with superoxide scavengers are resistant to GzmA. Here we find that GzmA accesses the mitochondrial matrix to cleave the complex I protein NDUFS3, an iron-sulfur subunit of the NADH:ubiquinone oxidoreductase complex I, after Lys56 to interfere with NADH oxidation and generate superoxide anions. Target cells expressing a cleavage site mutant of NDUFS3 are resistant to GzmA-mediated cell death but remain sensitive to GzmB.

Original languageEnglish (US)
Pages (from-to)681-692
Number of pages12
JournalCell
Volume133
Issue number4
DOIs
StatePublished - May 16 2008
Externally publishedYes

Keywords

  • CELLBIO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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