An integrated bioenergetics modeling approach to mitochondrial permeability transition
Acute myocardial infarctions are a result of the cessation of blood carrying vital nutrients and oxygen to the myocardium. This ischemic insult is detrimental to the affected tissue and resupplying the starved tissue with blood may result in a paradoxical response. This phenomenon is known as ischemia/reperfusion injury and is estimated contribute up to 50% of the infarct size. It often leads to a lethal reperfusion injury known as mitochondrial permeability transition (MPT). MPT is an event when a pore known as the mitochondrial permeability transition pore (PTP) opens and likely results in devastating bioenergetic consequences, namely cytochrome c mediated apoptosis and necrosis. Current therapies for MPT remain inadequate, and this fact highlights the need for understanding this ischemic/reperfusion injury in order to develop better therapeutic and preventative measures. The work presented in this thesis takes a step forward in this process and begins to unravel the MPT phenomenon at a bioenergetic mechanistic level in a mathematical modeling intensive manner. Three objectives of this work will be discussed: i) the development and corroboration of a mitochondrial bioenergetics model capable of modeling Ca2+ dynamics and volume regulation, ii) the extension of the bioenergetics model to include PTP regulation and analyze its affect on bioenergetics and iii) the development of a sampling based model-driven experiment design algorithm and its implementation in designing novel experiments to identify critical parameters for the adenine nucleotide translocase-based PTP voltage-sensor hypothesis.
Buzzard, Purdue University.
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