Mitochondrial dysfunction is often an underlying cause of myocardial disease. In particular, cardiac pathologies such as ischemia/reperfusion injury, heart failure, diabetic cardiomyopathy, anti-cancer agent-induced cardiotoxicity, etc., are associated with rapid and dramatic increases in mitochondrial permeability. These changes in permeability lead to ATP depletion, excessive production of reactive oxygen species, and ultimately swelling and rupture of the organelle, thereby instigating a molecular chain of events that leads to cardiomyocyte death. The long-range goal of our lab is to understand how specific mechanisms of mitochondrial-driven death can be targeted for the prevention of myocardial disease. The mitochondrial permeability transition (MPT) pore, a large, non-specific channel thought to span both mitochondrial membranes, is known to mediate the lethal permeability changes that initiate mitochondrial-driven death. However, with the exception of a protein called cyclophilin-D (CypD), the precise molecular componentry of the MPT pore has still not been defined.

 In order to identify new putative elements of the MPT pore, we have conducted genomic and proteomic screens of CypD-containing complexes. We are now employing a combinatorial approach that ranges from molecular and biochemical methodologies, through cell culture techniques, to studies in genetically engineered mice to assess the role of each candidate in MPT, cardiomyocyte death, and the pathogenesis of cardiac disease. In addition, MPT primarily drives necrotic cell death and thus another focus of our lab is studying mechanisms of programmed necrosis. In particular, we are concentrating on the so-called “necroptotic” pathway which is activated by TNF and induces a lethal kinase cascade consisting of RIP1, RIP3, and MLKL. We are examining the mechanisms by which this pathway is regulated and ultimately testing the role of these various components in the progression of cardiac disease. We are also studying how various necrotic pathways such as MPT, necroptosis, and PARP-driven necrosis are (or are not) coupled to one another.