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Redox regulation of endogenous substrate oxidation by cardiac mitochondria

Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California

Submitted 7 December 2005 ; accepted in final form 29 March 2006

Reactive oxygen species (ROS) play important roles in regulating mitochondrial function, as well as in ischemia-reperfusion injury and cardioprotection. Here we show that, in the absence of exogenous substrates, cardiac mitochondria have a surprisingly large capacity to phosphorylate ADP by oxidizing endogenous substrates, provided that H₂O₂ is removed from the extramitochondrial environment and a reduced environment is maintained in the matrix. In isolated mitochondria without exogenous substrates, addition of catalase and the membrane-permeant reducing agent N-acetylcysteine (Nac) or the ROS scavenger mercaptopropionyl glycine significantly increased the ability to phosphorylate added ADP, as demonstrated by 1) full recovery of membrane potential () and matrix volume from ADP-induced dissipation and shrinkage, 2) ADP-dependent increase in O₂ consumption, and 3) enhanced rate of ATP synthesis. Removal of extramitochondrial H₂O₂ by catalase was required to stimulate endogenous substrate oxidation, as shown by the increase in O₂ consumption and . This effect was greatly enhanced by addition of Nac or mercaptopropionyl glycine to suppress oxidation-induced ROS increases in the matrix. Theoretical considerations, as well as reversible inhibition of O₂ consumption with 3-mercaptopropionic acid and pyruvate in state 3, indicate that these substrates are fatty acids. Under in vivo conditions in which powerful antioxidant conditions are maintained, this mechanism may be important in stimulation of -oxidation and ATP production at low levels of extramitochondrial fatty acids. Incapacitation of this mechanism may potentially contribute to mitochondrial dysfunction during oxidative stress.

isolated mitochondria; redox environment; endogenous substrates; adenosine diphosphate phosphorylation