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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 May 20

PMID 18485875

Citations 93

Authors

Denis Martinvalet

Derek M Dykxhoorn

Roger Ferrini

Judy Lieberman

Affiliations

Soon will be listed here.

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 (DeltaPsi(m)) 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.

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