MITOCHONDRIAL FUNCTION IN ISCHEMIC HEART DISEASE

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DESCRIPTION (provided by applicant): While there are various etiologies of cardiovascular disease, it can be argued that a mismatch of energy supply and demand is a universal feature. Preservation of mitochondrial function is the single most important factor in determining whether a cardiac cell, and the organism, lives or dies, yet many questions about the control of metabolism remain unanswered. Moreover, ischemia causes remodeling of the control points of oxidative metabolism at the level of both substrate supply and the respiratory chain, and markedly alters intracellular ion homeostasis. All of these factors will significantly affect cardiac bioenergetics, but the relative importance of each in determining the recovery of the postischemic heart is unknown. Mitochondria also play a central role in counteracting the injury associated with ischemia and reperfusion, a fact that has recently been brought into sharp focus with the recognition that the phenomenon of preconditioning depends upon the activation of mitochondrial ion channels. An integrative approach is required to understand how the many ischemia-induced defects in metabolism contribute to the bioenergetic response of the wholeheart and survival after an acute ischemic attack. This Program Project garners the collective assets and experience of a multidisciplinary team of investigators at Johns Hopkins University to gain a detailed understanding of the central role of mitochondria in ischemic heart disease. The following major questions will be addressed: i ) what mechanisms and intracellular factors control the response of mitochondrial oxidative phosphorylation to changes in workload? ii) how is the structure (at the level of the proteome) and function of the mitochondria remodeled by ischemia and reperfusion, or preconditioning? iii) what are the principal mechanisms responsible for mitochondrial energetic failure? and iv) what are the key mitochondrial protein effectors of preconditioning? The Program is organized around a common rabbit model exposed to global ischemia-reperfusion, q preconditioning, and a strong computational model development core that will allow data to be interpreted within a central integrated simulation environment. The objectives include determining how the dynamics of cation (Ca2+, Na+, and K+) transfer from the cytoplasm to the mitochondria influence bioenergetics and force production (Project 1), examining the molecular effectors of cardioprotection mediated by mitochondrial inner membrane K+ channels (Project 2), defining how the mitochondrial proteome remodels during ischemia-reperfusion (Project 3) and how such changes influence the control of mitochondrial oxidative phosphorylation (Projects 1,3, and 4), and an investigation of the effects of ischemia and reperfusion on the mitochondrial ATP synthase and its regulatory protein partners (Projects 3,4).