MITOCHONDRIAL STRUCTURAL CHANGES IN CARDIOPROTECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ischemic preconditioning (IPC) is the most powerful protective mechanism known against subsequent infarction in both heart and brain. We have shown that diazoxide, a putative mitochondrial KATP (mito-KATP) opener, mimics the protective effects of IPC by 1) preventing mitochondrial permeability transition (MPT) and cell death by minimizing mitochondrial calcium overload and 2) inhibiting the release of cyto c from anoxic mitochondria [Korge, et al. PNAS 99:3312-17, 2002]. Recently, it has been shown that the mitochondrial structural changes may regulate cytochrome c release. The junctions between cristae and the intermembrane space widens during apoptosis, leading to cyto c release [Korsmeyer et al, Developmental Cell 1:515-25, 2001]. Together these observations support the view that mitochondrial structure and function determine the balance between cell life and cell death by either apoptosis (cyto c release) or necrosis (MPT). Our hypothesis is that both IPC and mito-KATP channel openers can preserve mitochondrial function during ischemia by inhibiting cyto c release and enhancing subsequent ATP production upon reperfusion by remodeling mitochondrial structure. It is well-accepted that addition of ADP to energized mitochondria leads to transient mitochondrial depolarization and matrix shrinkage associated with ATP production, followed by membrane potential and matrix volume recovery after ADP is consumed. We have discovered that serial additions of ADP to energized mitochondria in physiologic K concentrations lead to mitochondrial shrinkage and membrane potential dissipation that is not reversible after several ADP pulses. Both O2 consumption and membrane potential dissipation in response to ADP addition are significantly decreased, pointing to a failure of ADP/ATP exchange. We have experimental evidence that these functional changes resulting in decreased ADP production are connected to an imbalance between ion fluxes that are known to regulate mitochondrial volume. By using electron tomography, we wish to characterize the importance of mitochondrial structural remodeling (changes in intermembrane, matrix and cristal compartments) in the functional changes as described above. We postulate that ischemic preconditioning and KATP openers protect hearts against future injury by structural remodeling in mitochondria that allow for sustained ATP production.