3354 Sheu, Shey-Shing - Thomas Jefferson University
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, 2011 

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 2238 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. Isoform-specific dynamic translocation of PKC by α<inf>1</inf>-adrenoceptor stimulation in live cells
  2. Mitochondrial dynamics regulate neointima formation
  3. Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses
  4. Mitochondrial flash as a novel biomarker of mitochondrial respiration in the heart
  5. Solid-immersion fluorescence microscopy with increased emission and super resolution
  6. Cheng et al. reply
  7. Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling
  8. Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter
  9. Molecular and functional identification of a mitochondrial ryanodine receptor in neurons
  10. Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria
  11. Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts
  12. ADP protects cardiac mitochondria under severe oxidative stress
  13. Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting
  14. Respective contribution of mitochondrial Superoxide and ph to mitochondria-targeted circularly permuted yellow fluorescent protein (mt-cpYFP) flash activity
  15. Alpha1-adrenenoceptor stimulation inhibits cardiac excitation-contraction coupling through tyrosine phosphorylation of beta1-adrenoceptor
  16. Structural and Molecular Bases of Mitochondrial Ion Channel Function
  17. Mitochondria take center stage
  18. 23C7
  19. Molecular identities of mitochondrial Ca 2+ influx mechanism: Updated passwords for accessing mitochondrial Ca 2+-linked health: And disease
  20. Calcium transport across the inner mitochondrial membrane: Molecular mechanisms and pharmacology
  21. The 65th Symposium of the Society for General Physiologists: energizing research in mitochondrial physiology and medicine.