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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.