Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain.
Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (DeltaPsim), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis.
Ricci
Jean-Ehrland
JE
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Muñoz-Pinedo
Cristina
C
Fitzgerald
Patrick
P
Bailly-Maitre
Béatrice
B
Perkins
Guy A
GA
Yadava
Nagendra
N
Scheffler
Immo E
IE
Ellisman
Mark H
MH
Green
Douglas R
DR
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D045222:Electron Transport Chain Complex Proteins; C487793:NDUFS1 protein, human; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; D020169:Caspases; D042967:Electron Transport Complex I