Co - Mentor
Mitochondrial Protein Dynamics in Disease
The mitochondrion is a complex organelle that performs several critical functions, including serves as the central hub of eukaryotic energy metabolism. Its functions are intimately tied to its molecular and mesoscale structures, with certain enzymes, pumps, and transporters expressed in a tightly controlled stoichiometric balance and arranged as a spatially complex, dynamically regulated machine. Mitochondrial dysfunction underlies or is a major contributor to a large number of pathologies, including diabetes and obesity, cancer, and cardiovascular disease, yet the molecular basis for mitochondrial dysfunction is poorly understood. Post-translational (chemical) modifications (PTMs) of mitochondrial proteins may play a role in the functional changes but the low abundance of many of these changes suggest that other unknown mechanisms are involved. The overarching goal of this project is to realize a next-generation model of mitochondrial structure/function relationships, and understand how dynamic changes in macromolecular interactions contribute to mitochondria’s roles in physiology and disease. Toward these goals, we are applying new proteomic approaches assess how the organization of mitochondrial membrane proteins changes in response to calcium overload stemming from ischemia/reperfusion. Among our initial targets are the structural changes underlying the induction of the “permeability transition” that signals cell death in cerebral stroke and myocardial ischemia.