Mitochondria and ischemia/reperfusion injury.
Cardiac ischemia/reperfusion injury results in a variable mixture of apoptotic, necrotic, and normal tissue that depends on both the duration and severity of ischemia. Injury can be abrogated by activation of protective pathways via ischemic and pharmacologic preconditioning. Mitochondria serve as final arbiters of life and death of the cell as these organelles not only are required to generate ATP but also can trigger apoptosis or necrosis. A key mechanism of mitochondrial injury is by the mitochondrial permeability transition (MPT) that has been shown to occur at reperfusion. The article hypothesizes that ischemia/reperfusion promotes MPT in two phases: (1) MPT priming during ischemia occurs as progressive inner mitochondrial membrane leak is accompanied by depressed electron transport in the setting of fatty acid accumulation and loss of cytochrome c and antioxidants; and (2) Triggering of MPT at reperfusion is determined by the interplay of mitochondrial membrane potential (DeltaPsi(m)) with mitochondrial matrix Ca, reactive oxygen species, and pH. It has been found that strategies that promote mitochondrial recovery such as pharmacologic preconditioning by diazoxide are mediated by K(+)-dependent regulation of matrix volume and DeltaPsi(m), resulting in improved efficiency of ATP synthesis as well as prevention of cytochrome c loss. If mitochondria fail to recover, then MPT and hypercontracture can result as DeltaPsi(m) depolarization waves regeneratively cross the cell (0.1 to 0.2 microm/s).
Honda
Henry M
HM
Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095, USA.
Korge
Paavo
P
Weiss
James N
JN
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D008929:Mitochondria, Heart / Q000502:physiology*; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015221:Potassium Channels / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology*
D015221:Potassium Channels; D000255:Adenosine Triphosphate