Thomas Jefferson University
Sidney Kimmel Medical College
Department of Medicine

Sheu, Shey-Shing

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Shey-Shing Sheu

Shey-Shing Sheu, PhD

Contact Dr. Sheu

1020 Locust Street
Room 543D
Philadelphia, PA 19107

(215) 503-5152
(215) 503-5731 fax

Medical School

University of Chicago, Chicago IL
PhD University of Chicago, 1979


Department of Medicine, Cardiology, University of Chicago, Chicago, IL

University Appointment

Professor of Medicine
Department of Medicine, Division of Cardiology

Research & Clinical Interests

Mitochondria play a central role in numerous fundamental cellular processes ranging from ATP generation, Ca2+ homeostasis, reactive oxygen species (ROS) generation, and apoptosis. Disturbances in mitochondrial Ca2+ and ROS dynamics lead to the pathogenesis of ischemic heart disease, cardiac arrhythmias, heart failure, neurodegenerative diseases, diabetes, and aging. Our long-term research objective is to elucidate cellular and molecular mechanisms by which mitochondria control intracellular Ca2+ and ROS dynamics and translate these mechanisms to the function and dysfunction of the hearts. Current research efforts are to focus on two projects:

(1) Mechanisms of Mitochondrial Ca2+ Transport in Heart Cells

Our immediate efforts are to characterize the mitochondrial Ca2+ influx and efflux mechanisms in cardiac muscle cells and determine how these mechanisms regulate excitation-contraction-metabolism coupling. The hypothesis is that cardiac mitochondria contain a ryanodine-sensive and a cyclosporine-sensitive Ca2+ permeable channel that are responsible for a rapid uptake of Ca2+ into and a rapid release of Ca2+ out of mitochondria, respectively. These dynamic Ca2+ transport mechanisms regulate cardiac bioenergetics and Ca2+ signaling. Disruption of these Ca2+ transport mechanisms lead to heart failure.

(2) Crosstalk Signaling between Mitochondrial Ca2+ and ROS

Our long-term objective of this project is to establish a unified theory to describe crosstalk signaling between Ca2+ and ROS in cardiac muscle cells. The hypothesis is: an increased mitochondrial Ca2+ concentrations tip the balance of mitochondrial dynamics towards fission that increase the probability for opening mitochondrial permeability transition pores, which enhances ROS generation. The resulting oxidized environment leads to additional mitochondrial Ca2+ increases through redox-regulated Ca2+ transport mechanisms. Eventually, this high-gain positive feedback loop is counter balanced by Ca2+ and ROS activated mitochondrial Ca2+ efflux mechanisms.

We will use a multidisciplinary approach, encompassing single cell fluorescence confocal microscopy to measure cytosolic and mitochondrial Ca2+ concentrations, patch clamp to record L-type Ca2+ currents, and biochemical and molecular biological techniques to probe the mitochondrial Ca2+ transport proteins. This research will provide important information regarding the fundamental principles of mitochondrial Ca2+ transport mechanisms in heart cells. This information is critical for our understanding of the participation of mitochondria in the etiology of cardiovascular diseases such as cardiac arrhythmia, cardiomyopathy, and heart failure. Ultimately, it will provide insights to the design of novel mitochondria-targeted therapeutic agents for treating heart diseases.


Most Recent Peer-Reviewed Publications

  1. Electrophysiological properties of the mitochondrial permeability transition pores: Channel diversity and disease implication
  2. Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC: Part IV
  3. Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion
  4. Unsolved mysteries and controversies of mitochondria in the heart– A Virtual Special Issue in JMCC: Part III
  5. Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC: Part II
  6. The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress
  7. Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC
  8. Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?
  9. Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction
  10. Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop
  11. Trpm2 enhances physiological bioenergetics and protects against pathological oxidative cardiac injury: Role of Pyk2 phosphorylation
  12. Introduction
  13. SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2 influx, and regulation of mitochondrial permeability transition pore opening
  14. Mitochondrial Ca2+ concentrations in live cells: quantification methods and discrepancies
  15. SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca 2+ has a lot to say
  16. Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart
  17. Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart
  18. Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes
  19. Fluorescence digital imaging microscopy- spatial distribution of CA2+ and H+ in single cells
  20. Organellar Ion Channels and Transporters
  21. Mitochondrial Ca2+ and regulation of the permeability transition pore
  22. A novel fission-independent role of dynaminrelated protein 1 in cardiac mitochondrial respiration
  23. The mitochondrial Ca2+ uniporter: Structure, function, and pharmacology
  24. Strategic positioning and biased activity of the mitochondrial calcium uniporter in cardiac muscle
  25. Mitochondrial Flash: Integrative Reactive Oxygen Species and pH Signals in Cell and Organelle Biology