In the United States, there are more than 8 million people who have suffered from at least one acute myocardial infarction in their lifetime. One of the major injuries associated with myocardial infarction is lethal ischemia/reperfusion (I/R) injur. This type of injury manifests from a phenomenon known as mitochondrial permeability transition (MPT), a detrimental form of mitochondrial dysfunction. MPT results in myocardial apoptosis or necrosis and is linked to dysfunction in mitochondrial Ca2+ handling and oxidative stress. Only recently has MPT been accepted as being a physiological response to myocardial I/R injury, but there still remains a significant need to improve current clinical treatments. This proposal aims to quantify the biophysical phenomena and chemical kinetics associated with mitochondrial dysfunction and to elucidate the relationship between mitochondrial Ca2+ and ROS homeostasis with MPT induction under physiological and pathophysiological conditions, particularly I/R injury, in isolated guinea pig cardiac mitochondria. This synergistic computational/experimental approach will encompass computational modeling and experimental observation to help formulate and quantitatively test hypotheses related to mitochondrial dysfunction. In doing so, this study will facilitate a rational and mechanistic approach to identify new therapeutic targets and develop novel therapies to correct or prevent mitochondrial dysfunction under pathological conditions, particularly I/R injury. The main purpose of this project is to provide the Principal Investigator with assistance to establish his independence and obtain a tenure-track faculty position in order to setup a research program to elucidate the origin of mitochondrial dysfunction associated with mitochondrial Ca2+ dysregulation and oxidative stress. During the mentored phase, the applicant will develop the necessary experimental acumen to complement their modeling skill set and sustain an independent research career in the field of mitochondrial physiology and computational biology. The training will include operating state-of-the-art equipment to characterize the mitochondrial Ca2+ sequestration system and develop a model of ROS homeostasis for cardiac mitochondria. During the independent phase, the applicant will apply his recent experimental training to determine the mechanism(s) responsible for the loss in mitochondrial Ca2+ and ROS homeostasis and characterize how dysregulation in these signaling constituents lead to MPT resulting in catastrophic cellular and organ system failure. The work laid out in this project will move us one step closer to understanding the pathophysiology of MPT, and the model developed will be an invaluable tool for the development of novel therapeutics to help prevent or assuage the detrimental consequences of unmitigated MPT induction.
This project will combine the utility of computational modeling and the proven capacity of computational model-driven experimental design to determine the mechanistic role of calcium and oxidative stress in mitochondrial dysfunction. This integrated modeling study will help assist with the future development of therapeutic strategies to mitigate injury stemming from cardiac infarction and related pathologies and pave the way for the future development of bioenergetics-based models in the context of human disease.
|Blomeyer, Christoph A; Bazil, Jason N; Stowe, David F et al. (2016) Mg(2+) differentially regulates two modes of mitochondrial Ca(2+) uptake in isolated cardiac mitochondria: implications for mitochondrial Ca(2+) sequestration. J Bioenerg Biomembr 48:175-88|
|Moxley, Michael A; Beard, Daniel A; Bazil, Jason N (2016) Global Kinetic Analysis of Mammalian E3 Reveals pH-dependent NAD+/NADH Regulation, Physiological Kinetic Reversibility, and Catalytic Optimum. J Biol Chem 291:2712-30|
|Vinnakota, Kalyan C; Bazil, Jason N; Van den Bergh, Françoise et al. (2016) Feedback Regulation and Time Hierarchy of Oxidative Phosphorylation in Cardiac Mitochondria. Biophys J 110:972-80|
|Bazil, Jason N; Beard, Daniel A; Vinnakota, Kalyan C (2016) Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation. Biophys J 110:962-71|