Molecular examination of mitochondrial calcium control

Project: Research projectResearch Project

Description

Abstract Ca2+ elevations in the heart can serve as a signal for augmented energy output from the mitochondria bydirectly increasing the activity of the electron transport chain and associated dehydrogenases. However, at thesame time sustained elevations in Ca2+ that occurs acutely after myocardial infarction injury can causecardiomyocyte necrotic and apoptotic death through opening of the mitochondrial permeability transition pore(PTP). The mitochondrial Ca2+ uniporter (MCU) complex imports Ca2+ across the inner membrane into themitochondrial matrix where it can affect both energy production and PTP opening during acute ischemic injury.Hence the MCU complex and many of the more recently described genes that constitute it could be noveltherapeutic targets for drug design with the goal of reducing cardiomyocyte death or altering cardiac metabolicperformance. The genes that comprise the MCU were only recently identified in the past 4 years; hence thefield is still in its infancy with respect to genetically correlating mitochondrial Ca2+ regulation with cardiacphysiology and pathophysiology in vivo. Here we propose to use mice lacking many of these key molecularregulators of mitochondrial Ca2+ handling to decode and differentiate between physiological and pathologicalCa2+ signals at baseline and with disease. Our overarching goal is to examine how mitochondrial Ca2+ influxand efflux regulates cardiac life, death and metabolism. However, no single cardiac laboratory in our field hasthe underlying expertise to both characterize the complex biophysics of mitochondrial Ca2+ handling and at thesame time employ the necessary mouse genetics and cell biology to truly achieve the stated goals of thisproject. Hence, we have implemented a seamless collaborative dual-PI proposal that will be 50/50 effortbetween the Molkentin and Bers laboratory, to wed the very best in mouse molecular genetics and cardiacphysiology with innovative assessment of mitochondrial and intracellular Ca2+ imagining and PTP activity,respectively. Our Aims will be: 1) to characterize the function of the newly identified MCU complex genes aswell as other new genes underlying mitochondrial Ca2+ regulation the heart, 2) To assess MCU gene functionin underlying cardiac physiology, metabolism and after ischemic injury, and 3) To assess PTP dynamics andthe physiologic versus pathophysiologic states of the PTP in regulating mitochondrial Ca2+ and cell death. The2 PIs have a strong track record of working together with multiple shared publications and joint grants. Hence,they represent an ideal melding of 2 rather divergent laboratory skill sets that are needed to truly understandmitochondrial Ca2+ regulation and its effect on cardiac physiology and disease responsiveness.
StatusActive
Effective start/end date7/15/163/31/20

Funding

  • National Institutes of Health: $796,341.00

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Permeability
Calcium
Mitochondrial Genes
Wounds and Injuries
Genes
Biophysics
Organized Financing
Drug Design
Electron Transport
Cardiac Myocytes
Cell Biology
Publications
Molecular Biology
Heart Diseases
Mitochondria
Oxidoreductases
Cell Death
Myocardial Infarction
Membranes