CCBM Seminar Series
Brian O'Rourke
Associate Professor, Institute of Molecular Cardiobiology,
School of Medicine , The Johns Hopkins University , Baltimore MD
MITOCHONDRIA ON THE EDGE: CRITICALITY AND PERCOLATION IN THE MITOCHONDRIAL NETWORK
Reactive oxygen species (ROS) and/or Ca 2+ overload during ischemia-reperfusion can trigger depolarization of the mitochondrial inner membrane potential ( D Y m ) and cell injury or death; however, it is unknown whether loss of D Y m in a small number of mitochondria will impact the overall function of the cell. We have employed the narrow focal excitation volume of the two-photon microscope to determine if mitochondrial signals are propagated in guinea-pig ventricular myocytes. Remarkably, a single local laser flash (in <1% of the cell volume), after a delay, triggered synchronized and self-sustained oscillations in D Y m , NADH, and ROS (period ~1.5 min), in more than 70% of the mitochondrial population. Oscillations were initiated only after a specific threshold level of mitochondrially-produced ROS was exceeded, and did not involve t he classical permeability transition pore or intracellular Ca 2+ overload. The synchronized transitions were abolished by several respiratory inhibitors or a superoxide dismutase mimetic. Anion channel inhibitors potentiated matrix ROS accumulation in the flashed region, but blocked propagation to the rest of the myocyte, suggesting that an inner membrane, superoxide-permeable, anion channel opens in response to free radicals. Stable mitochondrial oscillation could also be demonstrated in silico, using a newly developed computer model of mitochondrial bioenergetics. Furthermore, such transitions in mitochondrial energetics could be demonstrated in intact hearts subjected to ischemia-reperfusion or oxidant stress. Because the mitochondrial transitions are tightly coupled to the activation of sarcolemmal K ATP currents, causing oscillations in action potential d u ration and regional inexcitability, they are likely to mediate catastrophic arrhythmias during ischemia-reperfusion injury.
Note: This seminar series is videoconferenced to Talbot library, Traylor building and to the Department of Bioengineering, UCSD. For information on videoconference bridging, or on disability access, contact Sunghee Flores at 410-516-4116 or sflores@bme.jhu.edu
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Thursday
October 23, 2003
4:00-5:00pm
Room 110,
Clark hall
Video Archive
[ 300kbps ] Real
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