Sheu Research
Contact
- William Wikoff Smith Professor of Cardiovascular Research,
- Associate Director
1020 Locust Street
543D
Philadelphia , PA 19107
The overall goal of our research is to elucidate the fundamental principles in complex cardiac health and disease through an integrated paradigm of mitochondrial Ca2+, ROS, and ATP co-operative signaling mechanisms in spatial and temporal micro-domains. Our research vision is to improve health and cur e disease through toning mitochondrial energetics, Ca2+, and redox signaling. We are currently addressing three fundamental questions in cardiovascular physiology and pathology.
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Dynamin-Related Protein (Drp1) Regulates Cardiac Excitation-Contraction-Bioenergetics Coupling
Fig.1: isolated mouse cardiomyocyte, IF confocal image (Airyscan), stained for DRP1 (green), RyR2 (red).
We hypothesize that during cardiac excitation-contraction (EC) coupling cycles, high Ca2+ concentrations in the micro-domain between junctional sarcoplasmic reticulum (jSR) and mitochondria contacts activate the mitochondrial fission protein, Drp1, to accumulate to the mitochondria-associated SR membrane (MAM) and form high molecular weight protein complexes. Through a yet to be elucidated mechanism, the oligomerized Drp1 in MAM stimulates mitochondrial ATP generation to sustain the energy currency for blood pumping. However, excessive Drp1 activation will lead to over-generation of ROS that causes persistent mitochondrial permeability transition pore opening (mPTP) and subsequent cell injury and death.
Structural-Functional Zoning of the Mitochondrion in Cardiac Ca2+, ROS, and Energetics Regulation
Fig.2 left: adult mouse cardiomyocytes labeled for mitochondria and sarcoplasmic reticulum, right: scheme showing the mitochondrial Ca signaling pathways in adult cardiomyocytes
The central hypothesis is that the sub-mitochondrial distribution (zoning) of Ca2+ transporters and cristae organization serves to adapt mitochondria for localized cell signaling, created by SR-mitochondria juxtaposition, for ensuring efficient and safe regulation of mitochondrial energetics and quality control.
Ca2+ and ROS Crosstalk Signaling in Cardiac Mitochondria
Fig. 3: “Love-Hate Triangle”: interconnection between calcium signaling, energy production and ROS generation in adult cardiomyocytes
The goal is to define how Ca2+ and mitochondrial dynamics regulate the opening of the permeability transition pores (PTP) distinctively and its implication in cardiac physio-pathology. Our central hypothesis is that cyclophilin D (CypD) phosphorylation induced by matrix Ca2+ is an essential event for PTP opening, whereas mitochondrial dynamics regulates a novel non-conventional transient PTP (nc-tPTP) opening, and their interplay (pull/push balance) determines cardiac pathologic state.