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A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury.
Woods, Joshua J; Nemani, Neeharika; Shanmughapriya, Santhanam; Kumar, Akshay; Zhang, MengQi; Nathan, Sarah R; Thomas, Manfred; Carvalho, Edmund; Ramachandran, Karthik; Srikantan, Subramanya; Stathopulos, Peter B; Wilson, Justin J; Madesh, Muniswamy.
Afiliação
  • Woods JJ; Robert F. Smith School for Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
  • Nemani N; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Shanmughapriya S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Kumar A; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Zhang M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Nathan SR; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Thomas M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Carvalho E; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Ramachandran K; Department of Physiology and Pharmacology, Western University, London, Ontario N6A 5C1, Canada.
  • Srikantan S; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Stathopulos PB; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Wilson JJ; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
  • Madesh M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.
ACS Cent Sci ; 5(1): 153-166, 2019 Jan 23.
Article em En | MEDLINE | ID: mdl-30693334
Mitochondrial Ca2+ (mCa2+) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca2+ dynamics and mitochondrial membrane potential (ΔΨm). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2019 Tipo de documento: Article