(1) 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 coupling. Our working hypothesis is that cardiac mitochondria contain a Ca²⁺-activated, ryanodine-sensive and a Ca²⁺-activated cyclosporin-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 coupling process, due to their structural proximity to the junctions between sarcoplasmic reticulum and L-type Ca²⁺ channels.

(2) Mitochondrial Ca²⁺ Transport in Hypertrophied and Failing Heart
Our main objective is to determine the role of mitochondrial Ca²⁺ transport underlying cardiac hypertrophy and heart failure. The working hypothesis is that a reduction in the magnitude of Ca²⁺ sequestration by mitochondria, either due to a displacement of mitochondria from Ca²⁺ release sites of sarcoplasmic reticulum and L-type Ca²⁺ channels and/or a defect in mitochondrial Ca²⁺ uptake mechanisms, leads to a reduction in cardiac contractility and ATP production (heart failure).

(3) Mitochondrial Modulation of Neuronal Excitotoxicity
Our immediate goal is to determine the role of mitochodrial 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.

(4) Mitochondrial Glutathione: Protection Against Spinal Cord Injury
In this proposal, we will test the hypothesis: "Enhancement of mitochondrial glutathione concentration ameliorates oxidative stress-induced damage to spinal cord neurons." The information obtained from the present investigation will not only test a unique hypothesis of how reactive oxygen species (ROS) mediates spinal cord injury (SCI) but will also provide new and novel strategies for the development of therapeutic agents for the treatment of SCI.

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.

Anders MW, Robotham JL, and Sheu S-S.  Mitochondria-targeted antioxidant prodrugs and methods of use.  US Provisional Patent Application, 2005.

Beutner G, Sharma VK, Lin L, Ryu SY, Dirksen RT, and Sheu S-S.  (2005)  Type 1 ryanodine receptor in cardiac mitochondria: Transducer of excitation-metabolism coupling.  Biochim. Biophys. Acta 1717:1-10.

Brookes PS, Sheu S-S, Anders MW.  Method for attenuating mitochondria-mediated cell injury.  US Provisional Patent Application, 2005.

Itoh S, Lemay S, Osawa M, Che W, Duan Y, Tompkins A, Brookes PS, Sheu S-S, and Abe J-I.  (2005)  Mitochondrial Dok-4 recruits SRC kinase and regulates NF-κB activation in endothelial cells.  J. Biol. Chem. 280:26383-96.

Watanabe T, Suzuki J, Yamawaki H, Sharma VK, Sheu S-S, and Berk BC.  (2005)  Losartan metabolite EXP3179 activates Akt and eNOS via VEGF receptor-2 in endothelial cells: AT1 receptor-independent effects of EXP3179.  Circulation 112:1798-805.

Anders MW, Robotham JL, Sheu S-S.  (2006)  Mitochondria: New drug targets for oxidative stress-induced diseases.  Expert Opin. Drug Metab. Toxicol., 2:71-79.

Brdiczka DG, Zorov DB, and Sheu S-S.  (2006)  Mitochondrial contact sites: Their role in energy metabolism and apoptosis.  Biochim. Biophys. Acta 1762:148-163.

Sheu S-S and Lemasters JJ.  (2006)  Special Issue: “Mitochondria in Diseases and Therapeutics”.  Biochim. Biophys. Acta 1762:139.

Sheu S-S, Nauduri D, and Anders, M.W.  (2006)  Targeting antioxidants to mitochondria: A new therapeutic direction.  Biochim. Biophys. Acta 1762:256-265.

Maekawa, N, Abe J-I, Itoh S, Ding B, Sharma VK, Sheu S-S, Blaxall BC, Berk BC.  Inhibiting p90 ribosomal S6 kinase prevents Na-H exchanger-mediated cardiac ischemia-reperfusion injury.  Circulation. 2006 (in press). 

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