Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death
Copyright policy )Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death
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.
- Harvard University United States
- University of Padua Italy
- University of Geneva Switzerland
PROTEINS, Oxidoreductases/metabolism, Liver/cytology, CELLBIO; PROTEINS; SIGNALING; Animals; Cell-Free System; Granzymes; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; HeLa Cells; Humans; Liver; Membrane Potential, Mitochondrial; Mice; Mitochondria; NADH Dehydrogenase; Oxidoreductases; Protein Transport; Reactive Oxygen Species; Recombinant Proteins; Rotenone; T-Lymphocytes, Cytotoxic; Uncoupling Agents; Cell Death; Biochemistry, Genetics and Molecular Biology (all), 612, NADH Dehydrogenase/metabolism, Granzymes, Granzymes/genetics/*metabolism, Mice, Reactive Oxygen Species/metabolism, Rotenone, Animals, Humans, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Recombinant Proteins/metabolism, Membrane Potential, Mitochondrial, Cell Death, Cell-Free System, Biochemistry, Genetics and Molecular Biology(all), Uncoupling Agents, Mitochondria/*chemistry/*metabolism, HSP70 Heat-Shock Proteins/metabolism, NADH Dehydrogenase, Recombinant Proteins, Mitochondria, Rotenone/pharmacology, Protein Transport, Liver, SIGNALING, CELLBIO, HSP90 Heat-Shock Proteins/metabolism, Uncoupling Agents/pharmacology, Oxidoreductases, Reactive Oxygen Species, *Cell Death/drug effects, T-Lymphocytes, Cytotoxic/enzymology, HeLa Cells, T-Lymphocytes, Cytotoxic, ddc: ddc:612
PROTEINS, Oxidoreductases/metabolism, Liver/cytology, CELLBIO; PROTEINS; SIGNALING; Animals; Cell-Free System; Granzymes; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; HeLa Cells; Humans; Liver; Membrane Potential, Mitochondrial; Mice; Mitochondria; NADH Dehydrogenase; Oxidoreductases; Protein Transport; Reactive Oxygen Species; Recombinant Proteins; Rotenone; T-Lymphocytes, Cytotoxic; Uncoupling Agents; Cell Death; Biochemistry, Genetics and Molecular Biology (all), 612, NADH Dehydrogenase/metabolism, Granzymes, Granzymes/genetics/*metabolism, Mice, Reactive Oxygen Species/metabolism, Rotenone, Animals, Humans, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Recombinant Proteins/metabolism, Membrane Potential, Mitochondrial, Cell Death, Cell-Free System, Biochemistry, Genetics and Molecular Biology(all), Uncoupling Agents, Mitochondria/*chemistry/*metabolism, HSP70 Heat-Shock Proteins/metabolism, NADH Dehydrogenase, Recombinant Proteins, Mitochondria, Rotenone/pharmacology, Protein Transport, Liver, SIGNALING, CELLBIO, HSP90 Heat-Shock Proteins/metabolism, Uncoupling Agents/pharmacology, Oxidoreductases, Reactive Oxygen Species, *Cell Death/drug effects, T-Lymphocytes, Cytotoxic/enzymology, HeLa Cells, T-Lymphocytes, Cytotoxic, ddc: ddc:612
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