Journal
CELL
Volume 133, Issue 4, Pages 681-692Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.03.032
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Funding
- NHLBI NIH HHS [T32 HL66987, T32 HL066987] Funding Source: Medline
- NIAID NIH HHS [AI45587, R01 AI045587-10, R01 AI045587, R56 AI045587] Funding Source: Medline
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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 (Delta Psi 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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