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Shey-Shing Sheu, Ph.D.

Contact Information

Phone Numbers

Office: (585) 275-3381

Fax: (585) 273-2652

Research Labs

Mitochondrial Ca2+ signaling, mitochondrial bioenergetics and reactive oxygen species in cell injury and death, mitochondrial targeted small molecules in cardiac and neuronal protection.

Lab: (585) 275-2704

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Professional Background

My long-term research objective is to elucidate an integrative mechanism by which mitochondria control intracellular Ca2+ homeostasis, energy metabolism, and reactive oxygen species (ROS) generation under both physiological and pathological conditions. Current research effort is to focus on the crosstalk Ca2+ signaling between mitochondria and sarcoplasmic reticulum during excitation-contraction coupling in normal and failing hearts. We use a multidisciplinary approach, encompassing single cell fluorescence confocal microscopy to measure cytosolic and mitochondrial Ca2+ concentrations, patch clamp to record ionic currents, biochemical and molecular biological techniques to probe the mitochondrial proteins, and organic chemistry to synthesize small molecules as mitochondria-targeted antioxidants. My major awards include the Established Investigatorship Award, Paul Yu Research Award, and Fellow of the American Heart Association. I am a member of American Heart Association, AAAS, Biophysical Society, Society for Neuroscience, and the American Society for Cell Biology. I have served in the grant review panels for Alzheimer's Association Research Award, American Heart Association, Veteran Administration Research Merit Award, National Science Foundation Research Grant, and Hong Kong Research Grants Council. I am currently served as the Chair of Research Committee, American Heart Association/Northeast Affiliate.


Mitochondria play a central role in numerous fundamental cellular processes ranging from ATP generation, Ca2+ homeostasis, reactive oxygen species (ROS) generation, and apoptosis. Deregulation of the mitochondrial Ca2+ and ROS homeostasis has been implicated in the pathogenesis of ischemic heart disease, cardiac arrhythmias, neurodegenerative diseases, diabetes, and aging. Our long-term research objective is to elucidate cellular and molecular mechanism by which mitochondria control intracellular Ca2+ and ROS dynamics under both physiological and pathological conditions. Current research efforts are to focus on three 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. Our working hypothesis is that cardiac mitochondria contain a Ca2+-activated, ryanodine-sensive and a Ca2+-activated cyclosporine-sensitive Ca2+ permeable channel that are responsible for the fast uptake of Ca2+ into and fast release of Ca2+ out of mitochondria, respectively. These dynamic Ca2+ transport systems participate actively in regulating cardiac excitation-contraction-metabolism coupling processes, due to their structural proximity to the junctions between sarcoplasmic reticulum and L-type Ca2+ channels.

(2) Crosstalk Signaling between Mitochondrial Ca2+ and ROS
Our long-term objective of this project is to establish a unified theory to describe the mechanisms of crosstalk signaling between Ca2+ and ROS in cardiac muscle cells, and to translate these signaling pathways to the physiology and pathology of cardiac function. Our central hypothesis is: an increased mitochondrial Ca2+ concentration tips the balance of mitochondrial dynamics towards fission that drives an increase in ROS generation. The resulting oxidized environment leads to additional mitochondrial Ca2+ increases. Eventually, this high-gain positive feedback loop is counter balanced by Ca2+ and ROS activated mitochondrial Ca2+ efflux mechanisms.

(3) Mitochondrial Modulation of Neuronal Excitotoxicity
Our immediate goal is to determine the role of mitochondrial Ca2+ overload and oxidative stress in neuronal cell death. Our working hypothesis is that Ca2+- and ROS-dependent mitochondrial permeability transition (MPT) opening is central to the process of excitotoxic cell death, and that energetically impaired cells are more susceptible to excitotoxic cell death because they have a higher likelihood of MPT occurrence in response to a given excitotoxic stimulus

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 and brain 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 as well as neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. Ultimately, it will provide insights to design novel targets for therapeutic intervention in these diseases.



BS | Taiwan - Non-Medical School

PhD | University of Chicago


Keynote Speaker, Internship Research Symposium, ORT Braude College, Karmiel, Israel.

Founding member, Mitochondrial Research & Innovation Group, University of Rochester.

2001 - Present
Fellow of the American Heart association (F.A.H.A.).

Paul N. Yu, M.D. Research Award, American Heart Association/NY State Affiliate.

Keynote Lecturer: The 5th Forum for Calcium and Cardiovascular Diseases, Osaka, Japan.

Founding member, Upstate New York Cardiac Electrophysiology Society.

1985 - 1990
American Heart Association Established Investigatorship Award.

1974 - 1977
University of Chicago Fellowship.

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Journal Articles

Wang W, Gong G, Wang X, Wei-LaPierre L, Cheng H, Dirksen RT, Sheu SS. "Mitochondrial Flash: Integrative Reactive Oxygen Species and pH Signals in Cell and Organelle Biology." Antioxidants & redox signaling.. 2016 Sep 20; 25(9):534-49. Epub 2016 Jul 14.

Jhun BS, Mishra J, Monaco S, Fu D, Jiang W, Sheu SS, O-Uchi J. "The mitochondrial Ca2+ uniporter: regulation by auxiliary subunits and signal transduction pathways." American journal of physiology. Cell physiology.. 2016 Jul 1; 311(1):C67-80. Epub 2016 Apr 27.

Gomez L, Thiebaut PA, Paillard M, Ducreux S, Abrial M, Crola Da Silva C, Durand A, Alam MR, Van Coppenolle F, Sheu SS, Ovize M. "The SR/ER-mitochondria calcium crosstalk is regulated by GSK3? during reperfusion injury." Cell death and differentiation.. 2016 Feb 0; 23(2):313-22. Epub 2015 Jul 24.