(Conferences / Seminars / Lectures)
"The Role of Mitochondrial Dysfunction in Ischemia/Reperfusion Injury" - Dr. Jason Bazil more information...
Ischemia/reperfusion (I/R) injury is the most significant cause of cell death resulting from a heart attack or stroke. How tissues respond to ischemia followed by reperfusion determines the outcome of critical events ranging from cardiopulmonary bypass surgery to hemorrhagic shock. And the primary pathway initiating cell death in high energy-demand tissues such as the heart, brain, and kidney centers on mitochondria. In all of these organs, an ischemic insult directly affects cellular and mitochondrial energetics, calcium handling, and free radical homeostasis. The subsequent reperfusion ultimately initiates apoptotic signaling cascades through mitochondrial dependent pathways triggered by calcium and reactive oxygen species. These consequences underlie certain clinical practices-for example, the use of cold cardioplegia used to metabolically arrest the heart prior to transplantation. Yet we lack an understanding of the relevant metabolic and signaling processes that is detailed enough to explain experimental observations, predict differential outcomes, and help guide therapeutics. A systems approach, using experiments to inform computational models and models to interpret and design relevant experiments, is necessary to expand our understanding of the biochemistry and physiology that underpin mitochondrial reperfusion injury. Using this approach, investigation of mitochondrial calcium fluxes and sequestration reveals a novel mechanism responsible for the protective effect of adenine nucleotides during mitochondrial calcium loading. Furthermore, systems analysis identifies the mechanism by which succinate accumulates in ischemic tissue and leads to the burst of free radicals observed during reperfusion.