Cardiac mitochondria (MITO) are critical mediators of myocardial injury during ischemia and reperfusion. During ischemia, MITO sustain damage that is mediated by the mitochondrial electron transport chain (ETC). Our previous work discovered two major mechanisms of ETC-driven injury to MITO during ischemia. First, the ETC itself is damaged at complex I and complex III. Second, the anti-apoptotic peptide bcl-2 is depleted from MITO. We found that when inhibitors were used to block the ETC during ischemia, this damage to MITO was prevented. More remarkably, when MITO were protected during ischemia, infarct size measured after REP was substantially reduced. As a result of the ETC-driven damage during ischemia, MITO become effectors of cardiomyocyte injury during reperfusion. We hypothesize that the two mechanisms of ETC-dependent ischemic damage dominate cardiac injury during reperfusion. At the onset of reperfusion, damaged MITO generates oxidative injury, undergo catastrophic permeability changes and activate cell death programs. The mechanisms leading to these injurious global responses are identified and will lead to strategies for therapeutic intervention during early and later periods of reperfusion. In preliminary work for this proposal, we found tha although the ETC has already sustained damage, intervention during reperfusion to directly manipulate mitochondrial function can decrease cardiac injury. We have focused on mechanism-driven approaches to directly modulate metabolism using pharmacologic and genetic modulation of mitochondrial function, including the use transient and partial blockade of complex I. The experimental approaches are designed to bypass upstream signaling cascades and instead directly interact with the ultimate target and effector of the cardiac injury, the MITO We propose that at the onset of reperfusion, resumption of oxidative metabolism by the damaged ETC with electron transport from complex I into complex III generates oxidants that lead to opening of the mitochondrial permeability transition pore and cell death.
Aim 1 identifies and studies sites within complexes I and III that generate the injury at reperfusion. We hypothesize that the ETC-dependent depletion of bcl-2 from MITO during ischemia leads to mitochondrial outer membrane permeation and the activation of programmed cell death during reperfusion.
Aim 2 studies the role of bcl-2 depletion in permeability transition-mediated cardiac injury during early reperfusion that may serve to reinforce complex I-driven activation. Myocytes protected by intervention during the initial phase of reperfusion remain susceptible to MITO- driven cell death during longer periods of reperfusion. We hypothesize that the persistence of MITO with ischemia-damaged ETC and bcl-2 depletion will drive maladaptive mitochondrial remodeling responses including autophagy and the disruption of the MITO fission/fusion balance as studied in Aim 3. This work critically explores the mechanisms of cardiac injury during reperfusion of ETC-mediated injury to MITO from ischemia, both direct oxidative injury from the damaged ETC and injury via downstream effectors of ETC- dependent damage including bcl-2.
Acute myocardial infarction is a major cause of morbidity and mortality in the Veteran population. Despite timely reperfusion of ST elevation myocardial infarcts (STEMI), myocardial salvage is optimized by additional treatment during reperfusion. Unfortunately, treatments that are the focus of initial clinical studies use therapies that exhibit impaired cardioprotection in te presence of co-morbid conditions including aging and diabetes that are prevalent in the Veteran population. This proposal studies the direct modulation of metabolism in cardiac mitochondria at the onset of reperfusion to limit cardiac damage. The strategy to directly target the effector of cardioprotection, the mitochondria, will better tailor treatment to the Veteran patient population.
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