Ca2+ elevations in the heart can serve as a signal for augmented energy output from the mitochondria by directly increasing the activity of the electron transport chain and select dehydrogenases. However, at the same time sustained elevations in Ca2+ that occurs acutely after myocardial infarction injury can cause cardiomyocyte 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 the mitochondrial 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 novel therapeutic targets for drug design with the goal of reducing cardiomyocyte death or altering cardiac metabolic performance. The genes that comprise the MCU were only recently identified hence the field is still in its infancy with respect to genetically correlating mitochondrial Ca2+ regulation with cardiac physiology and pathophysiology in vivo. Here we propose to use mice lacking some of these key molecular regulators of mitochondrial Ca2+ handling to decode and differentiate between physiological and pathological Ca2+ signals at baseline and with disease. Our overarching goal is to examine how mitochondrial Ca2+ influx and efflux regulates cardiac life, death and metabolism. However, no single cardiac laboratory in our field has the underlying expertise to both characterize the complex biophysics of mitochondrial Ca2+ handling and at the same time employ the necessary mouse genetics and cell biology to truly achieve the stated goals of this project. Hence, we are requesting to renew our collaborative dual-PI proposal that will be 50/50 effort between the Molkentin and Bers laboratory, to wed the very best in mouse molecular genetics and cardiac physiology with innovative assessment of mitochondrial and intracellular Ca2+ imagining and PTP activity, respectively.
Our Aims will be:
Aim 1 : Examine how MCUb and the MCU complex regulates myocyte [Ca]Mito to affect metabolism and PTP opening with IR injury, Aim 2: Elucidate NCLX regulation in cardiac function, PTP opening and cell death after IR injury, and Aim 3: Identify the alternate / slow [Ca]Mito influx effectors that operate independent of MCU in the heart. The 2 PIs have a strong track record of working together with multiple shared publications and joint grants. Hence, they represent an ideal melding of 2 divergent laboratory skill sets that are needed to truly understand mitochondrial Ca2+ regulation and its effect on cardiac physiology and disease responsiveness.
The relevance of this application is rooted in the fundamental translational biology of how mitochondrial calcium impacts myocyte death and metabolism, both of which are dramatically altered in heart failure or immediately after myocardial infarctino injury. The proposal will investigate the mechanisms and genes that alter intra-mitochondrial calcium levels. A better understanding of how we might reduce or inhibit dramatic increases in mitochondrial calcium after ischemic injury would lead to novel protective strategies, such that myocytes could be prevented from necrotic death.
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