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One or more keywords matched the following properties of Lemasters, John
overview I have a long-standing interest in hepatic ischemia-reperfusion (IR) injury, especially as it relates to organ preservation for transplantation. I and my colleagues were the first to show a prominent role for nonparenchymal cells in IR injury to cold-stored livers. Specifically, we showed that reperfusion after cold ischemic storage leads to killing of sinusoidal endothelial cells and activation of Kupffer cells. We were also pioneers in showing that onset of the mitochondrial permeability transition (MPT) then developed in hepatic parenchymal cells, leading to hepatic apoptosis, necrosis and graft failure, and we developed a variety of stratagems to ameliorate these injuries that are beginning to find clinical application. Overall, my laboratory has published over 350 papers in peer-reviewed journals plus more than 100 book chapters. Productive, long-term collaborations with both junior and senior colleagues contributed importantly to this success. My research interests continue to relate to mitochondrial and cellular bioenergetics, including studies of oxidative phosphorylation in isolated mitochondria, mitochondrial dysfunction in toxic, and hypoxic and reperfusion injury to liver and heart cells, and graft failure from preservation injury to livers stored for transplantation surgery. Our in vitro and in vivo studies of living cells and tissues have shown that mitochondrial calcium uptake, iron translocation from lysosomes to mitochondria, and oxidative stress promote the MPT. The MPT initially induces lysosomal degradation of mitochondria by autophagy, a selective process called mitophagy. However, excess MPT induction induces both necrotic cell death from ATP depletion and apoptosis due to cytochrome c release after mitochondrial swelling. For these projects, my laboratory extensively applies new techniques of quantitative laser scanning confocal and intravital multiphoton microscopy for physiological analysis of single cells and living organs. The lab also extensively employs Seahorse technology to measure respiration and glycolytic flux in cultured cells. Current projects are examining how iron mobilization from lysosomes to cytosol and then to mitochondria during cold ischemic liver storage sensitizes hepatocytes and nonparenchymal cells to adverse events after reperfusion, leading ultimately to injury and failure of liver grafts. Despite a detailed understanding of their metabolism, mitochondria often behave anomalously. In particular, global suppression of mitochondrial metabolism and metabolite exchange occurs in apoptosis, ischemia/hypoxia, alcoholic liver disease and aerobic glycolysis in cancer cells (Warburg effect). My lab is also examining and supporting the novel hypothesis that closure of voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane accounts for global mitochondrial suppression consistent with a role for VDAC as a dynamic regulator, or governator, of global mitochondrial function both in health and disease. In cancer cells, we showed that free tubulin causes closure of VDAC.
One or more keywords matched the following items that are connected to Lemasters, John
Item TypeName
Academic Article The mitochondrial permeability transition: from biochemical curiosity to pathophysiological mechanism.
Academic Article Activated Kupffer cells cause a hypermetabolic state after gentle in situ manipulation of liver in rats.
Academic Article Genetic manipulation of sinusoidal endothelial cells.
Academic Article Protective effect of nitrendipine against hypoxic injury in perfused livers from ethanol-treated rats.
Academic Article Functions of autophagy in normal and diseased liver.
Academic Article Alcohol-induced liver injury. The role of oxygen.
Academic Article Hypoxic hepatocellular injury.
Academic Article Centrilobular injury following hypoxia in isolated, perfused rat liver.
Academic Article Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity.
Academic Article Is there release of mitochondrial calcium in toxic injury?
Academic Article Polyphenols of Camellia sinenesis decrease mortality, hepatic injury and generation of cytokines and reactive oxygen and nitrogen species after hemorrhage/resuscitation in rats.
Academic Article Autophagy in alcohol-induced liver diseases.
Academic Article Role of free radicals in failure of fatty livers following liver transplantation and alcoholic liver injury.
Concept Liver Diseases, Alcoholic
Concept Liver Diseases
Award or Honor Receipt Inaugural Fellow
Award or Honor Receipt Councillor-at-Large
Academic Article A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease.
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