Cardio-protective Strategies of Mitochondria and Cell Death

Bio: Dr. Elizabeth Murphy received her PhD from the University of Pennsylvania in Biochemistry, followed by postdoctoral studies in Physiology and then an assistant research professor position at Duke University Medical Center. Before joining the NHLBI in 2006 as the head of the Cardiac Physiology Section, she was the head of the Cell Biology Group at the National Institute of Environmental Health Sciences. She became a Fellow of the American Heart Association in 2001 and a Fellow of the International Society for Heart Research in 2007; she received the NHLBI Award for Outstanding Mentorship in 2011. Dr. Murphy has authored or co-authored more than 200 papers and reviews. Dr. Murphy is a member of the American Heart Association-Council of Basic Cardiovascular Research, American Physiological Society, and International Society for Heart Research. She served as president of the International Society for Heart Research from 2016 to 2019. She serves as Deputy Editor of Circulation Research. She has been a North American Coordinator of a Leducq Transatlantic Network of Excellence on Targeting Mitochondria to Treat Heart Disease. She received the Peter Harris Research Achievement Award from the International Society for Heart Research in 2020.

Abstract: Cardiovascular disease is the leading cause of morbidity and mortality in the US. Mechanisms responsible for cardiomyocyte death are poorly understood and this directly impairs translation of cardioprotective drugs to the clinic. My laboratory uses a multipronged, interactive approach to elucidate the mechanisms responsible for cardiomyocyte death and to define cardioprotective strategies. It is widely hypothesized that an increase in cytosolic calcium initiates cell death by entering mitochondria on the mitochondrial calcium uniporter (MCU) to activate a large conductance channel in the inner mitochondrial membrane known as the permeability transition pore (PTP) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death (Bauer and Murphy Circ Res 2020). Strategies to reduce PTP opening either by inhibiting the PTP directly or inhibiting the rise in its activator, mitochondrial calcium, have been proposed. A major limitation of developing strategies to inhibit the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP. However, it is agreed that cyclophilin D (CypD), a matrix mitochondrial protein, is an activator of PTP. To gain insight into the PTP we are studying the role of CypD in activating PTP. We have defined several novel post-translational modifications (PTM) of CypD and demonstrate that these PTMs integrate multiple signaling pathways which regulate the activity of the PTP (Amanakis Cardiovas. Res 2020). We also examined the role of isomerase activity of CypD in regulating the activity of the PTP (Casin JMCC 2023).