Mitochondria play a central role in numerous fundamental cellular processes ranging from ATP generation, Ca²⁺ homeostasis, and apoptosis. Deregulation of the mitochondrial Ca²⁺ homeostasis and free radical production has been implicated in the development of neurodegenerative diseases, diabetes, cardiomyopathy, and aging. Our long-term research objective is to elucidate an integrative mechanism by which mitochondria control intracellular Ca²⁺ signaling and reactive oxygen species (ROS) generation under both physiological and pathological conditions.

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.

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. Thus our work can clarify how numerous environmental toxicants, such as heavy metals, cause cell death via mitochondrial disturbance.

Other research efforts in this laboratory, not so closely related to toxicology, are desccribed on my lab page. We seek to characterize the mitochondrial Ca2+ influx and efflux mechanisms in cardiac muscle cells and determine how these mechanisms regulate excitation-contraction coupling, as well as to determine the role of mitochondrial Ca2+ transport underlying cardiac hypertrophy and heart failure.

Recent Publications

Anders MW, Robotham JL, Sheu SS. 2006. Mitochondria: new drug targets for oxidative stress-induced diseases. Expert Opin Drug Metab Toxicol. Feb;2(1):71-79.

Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS. 2006. The voltage-dependent anion channel (VDAC): function in intracellular signalling, cell life and cell death. Curr Pharm Des. 12(18):2249-2270. Review

Maekawa N, Abe J, Shishido T, Itoh S, Ding B, Sharma VK, Sheu SS, Blaxall BC, Berk BC. 2006. Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury. Circulation. May 30;113(21):2516-2523

Sheu SS, Nauduri D, Anders MW. 2006. Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta. Feb;1762(2):256-265

Brdiczka DG, Zorov DB, Sheu SS. 2006. Mitochondrial contact sites: their role in energy metabolism and apoptosis. Biochim Biophys Acta. Feb;1762(2):148-163

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

Watanabe T, Suzuki J, Yamawaki H, Sharma VK, Sheu SS, Berk BC. 2005. Losartan metabolite EXP3179 activates Akt and endothelial nitric oxide synthase via vascular endothelial growth factor receptor-2 in endothelial cells: angiotensin II type 1 receptor-independent effects of EXP3179. Circulation. Sep 20;112(12):1798-1805.

Itoh S, Lemay S, Osawa M, Che W, Duan Y, Tompkins A, Brookes PS, Sheu SS, Abe J. 2005 . Mitochondrial Dok-4 recruits Src kinase and regulates NF-kappaB activation in endothelial cells. J Biol Chem. Jul 15;280(28):26383-26396.

Brookes PS, Yoon Y, Robotham JL, Anders MW, and Sheu SS. 2004. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. Oct;287(4):C817-833. Review.

He X, Liu Y, Sharma V, Dirksen RT, Waugh R, Sheu SS, and Min W. 2003. ASK1 Associates with Troponin T and Induces Troponin T Phosphorylation and Contractile Dysfunction in Cardiomyocytes. Am J Pathol. Jul;163(1):243-251.