Molecular Identification of the Mitochondrial Permeability Transaction Pore (MPTP)
The MPTP is a pore generated within the mitochondrial inner membrane, which dissipates the membrane potential needed to generate ATP. If prolonged opening occurs, a cell dependent on mitochondrial ATP to maintain homeostasis will die. MPTP-dependent cell death is the main form of cell death that takes place during ischemic injuries. In addition, inhibition of the pore is protective in various disease models including muscular dystrophy, neurodegenerative disorders, and aging. Although the mitochondrial matrix triggering protein, cyclophilin D (CypD), and the outer mitochondrial membrane regulators, Bax and Bak, have been identified, the actual inner membrane pore-forming component of the MPTP is still undefined. Using a combination of genetically engineered mice and cell culture models, our lab aims to identify the final piece of this long-standing molecular mystery.
Identification of Novel Regulators of Necrotic Cell Death
In the attempt to identify novel regulators of necrotic cell death, we have performed a gain-of-function genome-wide screen. As a result of these screening efforts, we have identified 306 cDNAs as putative inhibitors of regulated necrosis and another 381 cDNAs were found to be maladaptive to calcium overload. Following secondary validation, we have generated a short list of the most interesting candidates that we are currently pursuing in vivo. For the hits that translate in vivo, we aim to define their role in the cell death pathways.