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Professor and Director, Center for Cell Death, Injury & Regeneration
QF308
250140
843-792-2153
QE302
792-3530
Mechanisms of Cell Injury
jjlemaste@musc.edu
www.musc.edu/ccdir

Education
Yale University, B.A., Psychology, 1969
Johns Hopkins University, M.D., 1975
Johns Hopkins University, Ph.D., Cell Biology, 1975

Description of Program

My research interests concern the cellular and molecular mechanisms underlying hypoxic and toxic injury to liver and heart cells and organs stored for transplantation surgery.  In particular, my laboratory is applying new techniques of laser scanning confocal and multiphoton microscopy to characterize the physiology of single living cells, including the assessment of ion homeostasis, mitochondrial function, electrical potentials, oxygen and nitrogen free radical formation, membrane permeability and other biochemical parameters during the pathogenesis of lethal cell injury. 

Increased Ca²⁺, formation of reactive oxygen and nitrogen species, and oxidation of pyridine nucleotides and glutathione promote a phenomenon called the mitochondrial permeability transition (MPT) that, in turn, leads to mitochondrial depolarization and uncoupling of oxidative phosphorylation. Our studies in living cells show that the MPT initially induces the sequestration and lysosomal degradation of mitochondria by the process of autophagy, a selective process also called mitophagy. However, excess MPT induction induces both necrotic cell death and apoptosis during reperfusion injury, oxidative stress, excitotoxicity, calcium ionophore-induced toxicity, drug toxicity, exposure to tumor necrosis factor-alpha (TNFa) and Fas ligation to liver, heart, tumor, and brain cells. Inhibitors of the MPT, such as cyclosporin A, decrease or abolish cell killing in these models. Progression to apoptosis or necrosis after the MPT depends on the presence or absence, respectively, of ATP. Often, features of both apoptotic and necrotic cell death develop after death signals and toxic stresses. We introduce the term ‘‘necrapoptosis’’ to emphasize the shared pathways leading to both forms of cell death. These findings offer new strategies to rescue cells and tissues from irreversible toxic and ischemic injury.

We are also studying reperfusion injury to livers stored for transplantation surgery.  After periods of storage associated with graft failure after transplantation, we showed that reperfusion causes sinusoidal endothelial cells to lose viability and Kupffer cells (hepatic macrophages) to become activated.  Based on these findings, we developed a new solution, Carolina rinse solution, whose use during reperfusion reduces lethal endothelial injury greatly and improves graft survival dramatically.  Similarly, we are developing rinse solutions to decrease reperfusion-induced myocardial infarction. We are further pursuing mechanisms of Kupffer cell activation caused by ischemia/reperfusion, endotoxin, alcohol exposure and traumatic stress, particularly the roles played by calcium, endocytosis, adenosine receptors and protein kinases. More recently, we are characterizing ischemic preconditioning as a strategy of decreasing graft failure from preservation injury, especially in grafts harvested from non-heart beating cadaver donors and reduced-size liver grafts.

Selected Publications

Theruvath, T.P., M.C. Snoddy, Z. Zhong, and J.J. Lemasters (2008) Mitochondrial permeability transition in liver ischemia and reperfusion: role of c-Jun N-terminal kinase 2. Transplanation 85, 1500-1504.

Theruvath, T.P. C. Czerny, V.K. Ramshesh, Z. Zhong, K.D. Chavin, and J.J. Lemasters (2008) c-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation. American Journal of Transplantation, in press.

Uchiyama,A., J.-S. Kim, K. Kon, H. Jaeschke, K. Ikejima, S. Watanabe and J.J. Lemasters (2008) Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury. Hepatology, in press.

Theruvath, T.P., Z. Zhong, P. Pediaditakis, V.K. Ramshesh, R.T. Currin, A. Tikunov, E. Holmuhamedov and J.J. Lemasters (2008) Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition. Hepatology 47, 236-246.

Lemasters, J.J., and V.K. Ramshesh (2007) Imaging of mitochondrial polarization and depolarization with cationic fluorophores. Meth. Cell Biol. 80, 283-295.

Zhong, Z., T.P. Theruvath, R.T. Currin, P.C. Waldmeier and J.J. Lemasters (2007) NIM811, a mitochondrial permeability transition inhibitor, prevents mitochondrial depolarization in small-for-size rat liver grafts. Am. J. Transplant. 7, 1103-1111.

Kim, I., S. Rodriguez-Enriquez and J.J. Lemasters (2007) Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245–253.

Malhi, H., G.J. Gores and J.J. Lemasters (2006) Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31-S44.

Kim, J.-S., Y. Jin, and J.J. Lemasters (2006) Reactive oxygen species, but not Ca²⁺, trigger pH- and mitochondrial permeability transition-dependent killing of adult rat myocytes after ischemia/reperfusion. Am. J. Physiol. 290, H2024-H2034.

Lemasters, J.J., and E. Holmuhamedov (2006) Voltage-dependent anion channel (VDAC) as mitochondrial governator – thinking outside the box. Biochim. Biophys. Acta 1762, 181-190.

BRIEF DESCRIPTION

Cellular and molecular mechanisms of apoptosis and necrosis; organ preservation for transplantation surgery; mitochondrial physiology and pathophysiology, including mitochondrial permeability transition, mitophagy and calcium homeostasis; oxidative stress; ischemia/reperfusion; confocal and multiphoton microscopy of living cells.