Considering that the stores of ATP within the heart are sufficient to maintain contraction for only about 50 beats, it is clear that cardiac function directly depends on a high level of energy production that can be achieved only by continual mitochondrial substrate oxidation. Disruption of mitochondrial oxidative phosphorylation as a consequence of ischemia, reperfusion, toxic drugs or cardiac disease leads to cell injury and death, with the latter manifested as either necrosis or apoptosis. While there has been intense investigation of factors involved in the induction of injury or protection from it, as well as of the signaling pathways switched on during programmed cell death, there is very little information available about the earliest triggers of mitochondrial dysfunction. The central theme of this proposal is that metabolic stress initiates changes in mitochondrial inner membrane ion permeability with different degrees of severity that depend upon the opening of particular classes of inner membrane ion channel. Emerging evidence suggests that channels such as the cyclosporin-sensitive permeability transition pore, the Ca uniport and the mitochondrial ATP-sensitive potassium channel play fundamental roles in the life and death of the ardiomyocyte. In addition to these energy dissipating pathways, other classes of inner membrane ion channel exist, but have undefined functional roles. In this proposal, we will test the specific hypothesis that mitochondrial inner membrane anion channels are the primary mediators of redox oscillations, waves and metabolic signaling both within and between cardiomyocytes in the syncytium. Using conventional imaging, the unique capabilities of two-photon laser scanning microscopy, and advanced patch-clamp techniques, we will investigate the physiological mechanisms of mitochondrial communication and metabolic propagation from the level of the single mitochondrion to the intact heart. Understanding this important, but heretofore understudied, problem will ultimately lend insight into all aspects of cardiac pathophysiology.
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