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Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity.
Dong, Zhiwei; Shanmughapriya, Santhanam; Tomar, Dhanendra; Siddiqui, Naveed; Lynch, Solomon; Nemani, Neeharika; Breves, Sarah L; Zhang, Xueqian; Tripathi, Aparna; Palaniappan, Palaniappan; Riitano, Massimo F; Worth, Alison M; Seelam, Ajay; Carvalho, Edmund; Subbiah, Ramasamy; Jaña, Fabián; Soboloff, Jonathan; Peng, Yizhi; Cheung, Joseph Y; Joseph, Suresh K; Caplan, Jeffrey; Rajan, Sudarsan; Stathopulos, Peter B; Madesh, Muniswamy.
Affiliation
  • Dong Z; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Institute of Burn Research, Southwest Hospital,
  • Shanmughapriya S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Tomar D; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Siddiqui N; Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
  • Lynch S; Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
  • Nemani N; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Breves SL; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Zhang X; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Tripathi A; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Palaniappan P; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Riitano MF; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Worth AM; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Seelam A; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Carvalho E; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Subbiah R; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Jaña F; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Soboloff J; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Peng Y; Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038, PRC.
  • Cheung JY; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • Joseph SK; MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Caplan J; Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
  • Rajan S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. Electronic address: sudarsan@temple.edu.
  • Stathopulos PB; Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
  • Madesh M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. Electronic address: madeshm@temple.edu.
Mol Cell ; 65(6): 1014-1028.e7, 2017 Mar 16.
Article in En | MEDLINE | ID: mdl-28262504
ABSTRACT
Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS, and enhanced [Ca2+]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channels / Ion Channel Gating / Calcium / Reactive Oxygen Species / Calcium Signaling / Endothelial Cells / Mitochondrial Membranes / Mitochondria Type of study: Prognostic_studies Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2017 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channels / Ion Channel Gating / Calcium / Reactive Oxygen Species / Calcium Signaling / Endothelial Cells / Mitochondrial Membranes / Mitochondria Type of study: Prognostic_studies Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2017 Type: Article