Role of the mitochondrial permeability transition in myocardial disease.
Mitochondria play a key role in determining cell fate during exposure to stress. Their role during ischemia/reperfusion is particularly critical because of the conditions that promote both apoptosis by the mitochondrial pathway and necrosis by irreversible damage to mitochondria in association with mitochondrial permeability transition (MPT). MPT is caused by the opening of permeability transition pores in the inner mitochondrial membrane, leading to matrix swelling, outer membrane rupture, release of apoptotic signaling molecules such as cytochrome c from the intermembrane space, and irreversible injury to the mitochondria. During ischemia (the MPT priming phase), factors such as intracellular Ca2+ accumulation, long-chain fatty acid accumulation, and reactive oxygen species progressively increase mitochondrial susceptibility to MPT, increasing the likelihood that MPT will occur on reperfusion (the MPT trigger phase). Because functional cardiac recovery ultimately depends on mitochondrial recovery, cardioprotection by ischemic and pharmacological preconditioning must ultimately involve the prevention of MPT. Investigations into this area are beginning to unravel some of the mechanistic links between cardioprotective signaling and mitochondria.
Weiss
James N
JN
Cardiovascular Research Laboratory, Department of Medicine (Cardiology), David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095-1760, USA. jweiss@mednet.ucla.edu
Korge
Paavo
P
Honda
Henry M
HM
Ping
Peipei
P
D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology*; D003574:Cytochrome c Group / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology*; D008929:Mitochondria, Heart / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism
D003574:Cytochrome c Group; D017382:Reactive Oxygen Species; D002118:Calcium