Cardiac ischemia/reperfusion, aging, and redox-dependent alterations in mitochondrial function
Section snippets
Overview
Coronary atherosclerosis is a prevalent disease which results in diminished arterial diameter and decrease in blood supply to myocardial tissue. Patients suffering from coronary artery disease exhibit depletion of myocardial O2 and ATP content when demand increases as with exertion (stable angina) or upon acute occlusion (unstable angina). Nevertheless, depending on the duration and extent of ischemia, restoration of blood flow to seemingly viable myocardial tissue is often accompanied by
Background
Reducing equivalents in the form of NADH and FADH2 produced through the function of the Krebs cycle enter the electron transport chain through complex I and complex II, respectively. Electrons are then transferred through a series of redox couples with the final electron acceptor being O2 leading to the formation of H2O. The energy that is liberated in the process of passing electrons to successively lower reduction potentials is utilized to pump protons from the mitochondrial matrix into the
Regulation of superoxide anion formation
Ischemia- and reperfusion-induced losses in electron transport chain enzyme activity and components have been discussed primarily in the context of the contribution these events may have to increased rates of free radical generation. While this is a valid hypothesis, particularly in cases were the block is established distal to known sites of free radical generation, the case of complex I inhibition requires careful consideration. If complex I inhibition prevents the entry of reducing
Background
The Krebs cycle is composed of eight enzymes, which oxidize metabolites supplied primarily from fatty acid, glucose, and amino acid catabolism. This results in the formation of reducing equivalents required for electron transport and thus ATP synthesis. The rate limiting step in ATP synthesis is the supply of reducing equivalents in the form of NADH to the electron transport chain [72], [73], [74]. Thus, while the electron transport chain is likely to play a key role in oxygen radical
Aging and cardiac ischemia/reperfusion
Aging is associated with an increase in myocardial dysfunction during reperfusion [96], [97], [98], [99]. Therefore, if mitochondria and free radicals play a significant role in alteration in function during cardiac ischemia/reperfusion, the effects should be more evident in aged animals when compared to their adult counterparts. Results from an isolated rat heart model indicate that ischemia/reperfusion induced declines in NADH-linked ADP-dependent respiratory rates and in complex I, complex
Acknowledgements
Work in the Szweda laboratory is supported by Grants AG-19357 and AG-16339 from the National Institutes of Health and an Established Investigator Grant from the American Heart Association (0040007N).
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