John J. Lemasters

Medical University of South Carolina, Charleston, South Carolina, United States

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Publications (448)2349.77 Total impact

  • Gastroenterology 05/2015; 148(4):1010. DOI:10.1016/S0016-5085(15)33449-1 · 16.72 Impact Factor
  • Gastroenterology 05/2015; Volume 148,(4):1010. DOI:10.1016/S0016-5085(15)33381-3 · 16.72 Impact Factor
  • Yasodha Krishnasamy · Zengdun Shi · John J. Lemasters · Don C. Rockey · Zhi Zhong
    Gastroenterology 04/2015; 148(4):S-1011. DOI:10.1016/S0016-5085(15)33453-3 · 16.72 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-989. DOI:10.1016/S0016-5085(15)33379-5 · 16.72 Impact Factor
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    ABSTRACT: Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Livers explanted from wild-type, iNOS(-/-), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS-deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS-deficiency. JNK inhibition and JNK2-deficiency, but not JNK1-deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS-deficiency, JNK inhibition and JNK2-deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization and is an attractive target to improve liver function and survival in CDD liver transplantation. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 02/2015; DOI:10.1016/j.jhep.2015.02.017 · 11.34 Impact Factor
  • Li Li · John J. Lemasters
    Biophysical Journal 01/2015; 108(2):327a. DOI:10.1016/j.bpj.2014.11.1781 · 3.97 Impact Factor
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    ABSTRACT: Hepatocytes exposed to ischemia/reperfusion (I/R) succumb to cell death after reperfusion. Sphingosine and ceramide profiles revealed substantial accumulation of sphingosine after 4h of ischemia to rat hepatocytes, whereas other sphingoid bases did not change. A lysosomotropic inhibitor of acid ceramidase suppressed I/R-induced death, indicating a lysosomal origin of sphingosine. Addition of exogenous sphingosine to hepatocytes increased cell death, which was insensitive to the ceramide synthase inhibitor, fumonisin B1. This finding indicates that accumulation of sphingosine, not ceramide formed from sphingosine, promoted cell death. Exogenous sphingosine also inhibited complex IV (cytochrome oxidase), the terminal component of the respiratory chain, in isolated mitochondria. Accordingly, we hypothesized that downstream respiratory inhibition by sphingosine leads to increased formation of O2•- radicals after reperfusion, which by themselves have only a moderately harmful effect. However when Fe2+ redistributes from lysosomes into mitochondria during ischemia, Fenton chemistry occurs after reperfusion, leading to formation of highly reactive OH• radicals, potent inducers of the mitochondrial permeability transition pore and cell death. This hypothesis was directly tested using bafilomycin, which induces the release of Fe2+ from lysosomes with subsequent uptake into mitochondria. Indeed, bafilomycin potentiated sphingosine-induced cell death. The data highlight a novel mechanism mediating I/R injury, which involves sphingosine accumulation and uptake of lysosomal iron into mitochondria during ischemia, leading to respiratory chain inhibition, iron-dependent oxidative stress, mitochondrial permeability transition and cell death after reperfusion. DK073336, DK037034 and 14.Z50.31.0028 (JJL) and NS083544 (TIG).
    Biophysical Journal 01/2015; 108(2):611a-612a. DOI:10.1016/j.bpj.2014.11.3327 · 3.97 Impact Factor
  • John J. Lemasters
    Biophysical Journal 01/2015; 108(2). DOI:10.1016/j.bpj.2014.11.032 · 3.97 Impact Factor
  • Biophysical Journal 01/2015; 108(2):189a. DOI:10.1016/j.bpj.2014.11.1047 · 3.97 Impact Factor
  • Eduardo N. Maldonado · Monika Gooz · David N. DeHart · John J. Lemasters
    Biophysical Journal 01/2015; 108(2):369a. DOI:10.1016/j.bpj.2014.11.2021 · 3.97 Impact Factor
  • Journal of the American Society of Nephrology 11/2014; 25:389A. · 9.34 Impact Factor
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    ABSTRACT: Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as /`accidental cell death/' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. /`Regulated cell death/' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects i
    Cell death and differentiation 09/2014; DOI:10.1038/cdd.2014.137 · 8.18 Impact Factor
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    Eduardo N Maldonado · John J Lemasters
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    ABSTRACT: Non-proliferating cells generate the bulk of cellular ATP by fully oxidizing respiratory substrates in mitochondria. Respiratory substrates cross the mitochondrial outer membrane through only one channel, the voltage dependent anion channel (VDAC). Once in the matrix, respiratory substrates are oxidized in the tricarboxylic acid cycle to generate mostly NADH that is further oxidized in the respiratory chain to generate a proton motive force comprised mainly of membrane potential (ΔΨ) to synthesize ATP. Mitochondrial ΔΨ then drives release of ATP(-4) from the matrix in exchange for ADP(-3) in the cytosol via the adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane. Thus, mitochondrial function in non-proliferating cells drives a high cytosolic ATP/ADP ratio, essential to inhibit glycolysis. By contrast, the bioenergetics of the Warburg phenotype of proliferating cells is characterized by enhanced aerobic glycolysis and suppression of mitochondrial metabolism. Suppressed mitochondrial function leads to lower production of mitochondrial ATP and hence lower cytosolic ATP/ADP ratios that favor enhanced glycolysis. Thus, cytosolic ATP/ADP ratio is a key feature that determines if cell metabolism is predominantly oxidative or glycolytic. Here, we describe two novel mechanisms to explain the suppression of mitochondrial metabolism in cancer cells: the relative closure of VDAC by free tubulin and inactivation of ANT. Both mechanisms contribute to low ATP/ADP ratios that activate glycolysis.
    Mitochondrion 09/2014; 19. DOI:10.1016/j.mito.2014.09.002 · 3.25 Impact Factor
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    ABSTRACT: First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.
    Biomedecine [?] Pharmacotherapy 08/2014; 68(7). DOI:10.1016/j.biopha.2014.08.007 · 2.02 Impact Factor
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    Biochimica et Biophysica Acta (BBA) - Bioenergetics 07/2014; 1837:e111. DOI:10.1016/j.bbabio.2014.05.267 · 5.35 Impact Factor
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics 07/2014; 1837:e112-e113. DOI:10.1016/j.bbabio.2014.05.271 · 5.35 Impact Factor
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    ABSTRACT: Ca(2+)-induced permeability transition pore (mPTP) opening in isolated rat brain mitochondria is promoted through targeting of connexin43. After a threshold Ca(2+) load, mitochondrial membrane potential drops and efflux of accumulated Ca(2+) from the mitochondrial matrix occurs, indicating the mPTP opening. Specific antibodies were used to assess the role of the translocator protein (18 kDa; TSPO) and connexin43 in swelling of isolated rat liver and brain mitochondria induced by carbenoxolone and the endogenous TSPO ligand protoporphyrin IX. Mitochondrial membrane potential, Ca(2+) transport and oxygen consumption were determined using selective electrodes. All the parameters were detected simultaneously in a chamber with the selective electrodes. The phosphorylation state of mitochondrial protein targets was assessed. We report that Ca(2+)-induced mitochondrial swelling was strengthened in the presence of both carbenoxolone and protoporphyrin IX. The carbenoxolone- and protoporphyrin IX-accelerated mPTP induction in brain mitochondria was completely prevented by antibodies specific for the mitochondrial translocator protein (TSPO). The anti-TSPO antibodies were more effective than anti-сonnexin43 antibodies. Moreover, carbenoxolone-stimulated phosphorylation of mitochondrial proteins was inhibited by anti-TSPO antibodies. Taken together, the data suggests that, in addition to acting via connexion43, carbenoxolone may exert its effect on mPTP via mitochondrial outer membrane TSPO.
    Archives of Biochemistry and Biophysics 07/2014; 558. DOI:10.1016/ · 3.02 Impact Factor
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    ABSTRACT: Background: Despite recovery of hemodynamics by fluid resuscitation after hemorrhage, development of the systemic inflammatory response and multiple organ dysfunction syndromes can nonetheless lead to death. Minocycline and doxycycline are tetracycline derivatives that are protective in models of hypoxic, ischemic, and oxidative stress. Our aim was to determine whether minocycline and doxycycline protect liver and kidney and improve survival in a mouse model of hemorrhagic shock and resuscitation. Methods: Mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood followed by half the shed volume of lactated Ringer's solution containing tetracycline (10 mg/kg), minocycline (10 mg/kg), doxycycline (5 mg/kg), or vehicle. For pretreatment plus posttreatment, drugs were administered intraperitoneally prior to hemorrhage followed by second equal dose in Ringer's solution after blood resuscitation. Blood and tissue were harvested after 6 h. Results: Serum alanine aminotransferase (ALT) increased to 1,988 and 1,878 U/L after posttreatment with vehicle and tetracycline, respectively, whereas minocycline and doxycycline posttreatment decreased ALT to 857 and 863 U/L. Pretreatment plus posttreatment with minocycline and doxycycline also decreased ALT to 849 and 834 U/L. After vehicle, blood creatinine increased to 134 µM, which minocycline and doxycycline posttreatment decreased to 59 and 56 µM. Minocycline and doxycycline pretreatment plus posttreatment decreased creatinine similarly. Minocycline and doxycycline also decreased necrosis and apoptosis in liver and apoptosis in both liver and kidney, the latter assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) and caspase 3 activation. Lastly after 4.5 h of hemorrhage followed by resuscitation, minocycline and doxycycline (but not tetracycline) posttreatment improved 1-week survival from 38% (vehicle) to 69% and 67%, respectively. Conclusion: Minocycline and doxycycline were similarly protective when given before as after blood resuscitation and might therefore have clinical efficacy to mitigate liver and kidney injury after resuscitated hemorrhage.
    Shock (Augusta, Ga.) 06/2014; 42(3). DOI:10.1097/SHK.0000000000000213 · 3.05 Impact Factor
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    John J. Lemasters
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    ABSTRACT: Mitophagy (mitochondrial autophagy), which removes damaged, effete and superfluous mitochondria, has several distinct variants. In Type 1 mitophagy occurring during nutrient deprivation, preautophagic structures (PAS) grow into cup-shaped phagophores that surround and sequester individual mitochondria into mitophagosomes, a process requiring phosphatidylinositol-3-kinase (PI3K) and often occurring in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies, followed by mitochondrial depolarization and ultimately hydrolytic digestion in lysosomes. Mitochondrial damage stimulates Type 2 mitophagy. After photodamage to single mitochondria, depolarization occurs followed by decoration and then coalescence of autophagic LC3-containing structures on mitochondrial surfaces. Vesicular acidification then occurs. By contrast to Type 1 mitophagy, PI3K inhibition does not block Type 2 mitophagy. Further, Type 2 mitophagy is not associated with phagophore formation or mitochondrial fission. A third form of self-eating of mitochondria is formation of mitochondria-derived vesicles (MDVs) enriched in oxidized mitochondrial proteins that bud off and transit into multivesicular bodies. Topologically, the internalization of MDV by invagination of the surface of multivesicular bodies followed by vesicle scission into the lumen is a form of microautophagy, or micromitophagy (Type 3 mitophagy). Cell biological distinctions are the basis for these three types of mitophagy. Future studies are needed to better characterize the molecular and biochemical differences between Types 1, 2 and 3 mitophagy.
    06/2014; 2(1). DOI:10.1016/j.redox.2014.06.004
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    ABSTRACT: Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88-/- mice and collecting duct epithelia cell from Ift88orpk mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay and a growth factor shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in cystic kidney and in collecting duct epithelial cells originating from the Ift88orpk mice (designated as PKD cells) leads to constitutive shedding of several growth factors including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and transforming growth factor-alpha (TGFα). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared to control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect) that was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a pro-proliferative glycolytic phenotype.
    American journal of physiology. Renal physiology 06/2014; 307(5). DOI:10.1152/ajprenal.00218.2014 · 3.25 Impact Factor

Publication Stats

24k Citations
2,349.77 Total Impact Points


  • 2006–2015
    • Medical University of South Carolina
      • • Department of Drug Discovery and Biomedical Sciences
      • • Center of Cell Death, Injury and Regeneration
      • • Department of Biochemistry and Molecular Biology (College of Medicine)
      Charleston, South Carolina, United States
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2010
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
  • 1978–2008
    • University of North Carolina at Chapel Hill
      • • Center for Gastrointestinal Biology and Disease
      • • Department of Nutrition
      • • Department of Surgery
      • • Department of Pharmacology
      • • Department of Medicine
      North Carolina, United States
  • 1996
    • University of Pavia
      Ticinum, Lombardy, Italy
  • 1995
    • University of Louisiana at Monroe
      Монро, Louisiana, United States
  • 1993
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Рочестер, Minnesota, United States
  • 1990
    • Universität des Saarlandes
      Saarbrücken, Saarland, Germany
  • 1983
    • University of North Carolina at Charlotte
      Charlotte, North Carolina, United States
  • 1973
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1971
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States