Mitochondrial fission leads to Smac/DIABLO release quenched by ARC.
Apoptosis plays a critical role for the development of a variety of cardiac diseases. Cardiomyocytes are enriched in mitochondria, while mitochondrial fission can regulate apoptosis. The molecular mechanism governing cardiomyocyte apoptosis remain to be fully elucidated. Our results showed that Smac/DIABLO is necessary for apoptosis in cardiomyocytes, and it is released from mitochondria into cytosol in response to apoptotic stimulation. Smac/DIABLO release is a consequence of mitochondrial fission mediated by dynamin-related protein-1 (Drp1). Upon release Smac/DIABLO binds to X-linked inhibitor of apoptosis protein (XIAP), resulting in the activation of caspase-9 and caspase-3. Their activation is a prerequisite for the initiation of apoptosis because the administration of z-LEHD-fmk and z-DQMD-fmk, two relatively specific inhibitors for caspase-9, and caspase-3, respectively, could significantly attenuate apoptosis. Smac/DIABLO release could not be blocked by these caspase inhibitors, indicating that it is an event upstream of caspase activation. ARC (apoptosis repressor with caspase recruitment domain), an abundantly expressed apoptotic repressor in cardiomyocytes, could inhibit mitochondrial fission and Smac/DIABLO release. Our data reveal that Smac/DIABLO is a target of ARC in counteracting apoptosis.
Li
Jincheng
J
Department of Physiology, Shantou University School of Medicine, Shantou, 515031, China.
Li
Yanrui
Y
Qin
Danian
D
von Harsdorf
Ruediger
R
Li
Peifeng
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; D053453:Caspase 9; C519851:Dnm1l protein, rat; D034281:Dynamins