title: Mitochondrial Ca2+Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity.
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+]muptake rate, elevated mROS, and enhanced [Ca2+]moverload-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.
authors.affiliation: 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, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.affiliation: 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.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
authors.forename: Naveed
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
authors.forename: Solomon
authors.initials: S
authors.lastname: Lynch
authors.affiliation: 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.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Nemani
authors.affiliation: 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.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Breves
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Aparna
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: 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.
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Palaniappan
authors.affiliation: 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.
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Riitano
authors.affiliation: 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.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Worth
authors.affiliation: 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.
authors.forename: Ajay
authors.initials: A
authors.lastname: Seelam
authors.affiliation: 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.
authors.forename: Edmund
authors.initials: E
authors.lastname: Carvalho
authors.affiliation: 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.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Subbiah
authors.affiliation: 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.
authors.forename: Fabián
authors.initials: F
authors.lastname: Jaña
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Soboloff
authors.affiliation: Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Joseph
authors.affiliation: Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Caplan
authors.affiliation: 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.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Stathopulos
authors.affiliation: 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.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death; D015687:Cell Hypoxia; D002522:Chlorocebus aethiops; D003545:Cysteine; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D015220:Calcium Channels; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D013917:Thrombin; D005978:Glutathione; D003545:Cysteine; D002118:Calcium
keywords: EMRE; MCU; MCUR1; MICU1; MICU2; bioenergetics; calcium; gluathionylation; mitochondria; reactive oxygen species