The Molecular Regulation of Adenine Nucleotide Translocase Proteins in Necrotic Cell Death, Metabolism, and Mitophagy
The Adenine nucleotide translocase (ANT) proteins are core metabolic proteins which exchange ATP/ADP between the mitochondria and cell to support cellular energy production. However, ANT proteins are also critical regulators of the mitochondrial membrane permeability transition pore (MPTP) which is the key molecular effector of necrotic cell death in diseases such as cardiac ischemia reperfusion injury and muscular dystrophy. ANT proteins have also been demonstrated to be important for mitophagy, the process of mitochondrial quality control, and muscle thermogenesis. We are interested in learning how ANT proteins are able to participate in these diverse processes and the molecular regulation that controls the switch from pro-survival metabolic functions to pathological cell death processes. We are utilizing genetically engineered dystrophic mice, gene therapy viral vectors, and molecular biology approaches to discover the ANT protein cell death trigger. The goal of this research is to generate new treatments for necrotic diseases such as muscular dystrophy, cardiovascular disease, and Alzheimer’s disease.
Determining a Complete Molecular Model of Mitochondrial Calcium Transport
Mitochondrial calcium (Ca2+) transport is a major regulator of mitochondrial function. When in the physiological range, Ca2+ uptake promotes oxidative energy production and mitochondrial fitness. However, excessive mitochondrial Ca2+ uptake activates cell death pathways and contributes to diseases such as cardiac ischemia reperfusion injury, muscular dystrophy, and neurodegenerative disease. The current model of mitochondrial Ca2+ transport focuses on the role of the mitochondrial calcium uniporter (MCU)-complex and the Na+/Ca2+ exchanger, however this model is incomplete. We and others have recently proved that mitochondria have MCU-independent Ca2+ uptake mechanisms which are sufficient to cause disease. Moreover, there are unidentified mitochondrial Ca2+ efflux pathways with which can compensate in the absence of NCLX. We are currently working to identify the basis of MCU-independent Ca2+ uptake, to prove the molecular identity of the mitochondrial H+/Ca2+ exchanger, and to create a comprehensive model of mitochondrial Ca2+ transport using molecular, cellular, and animal physiology approaches. Our goal is to leverage this new model of mitochondrial Ca2+ transport to develop new therapies for cardiovascular disease, muscular dystrophy, and neurodegenerative disease.
