Mitochondrial Ca 2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

• Published in: Molecular cell Vol. 65; no. 6; p. 1014
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 16.03.2017
• Subjects: Animals; Calcium - metabolism; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Signaling - drug effects; Cell Death; Cell Hypoxia; Cercopithecus aethiops; COS Cells; Cysteine; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Energy Metabolism; Glutathione - metabolism; HEK293 Cells; HeLa Cells; Humans; Ion Channel Gating - drug effects; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mitochondrial Membranes - pathology; Mutation; Oxidation-Reduction; Protein Multimerization; Protein Processing, Post-Translational; Protein Structure, Quaternary; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Thrombin - pharmacology; Time Factors; Transfection; MCUR1; calcium; bioenergetics; mitochondria; reactive oxygen species; EMRE; MICU2; MICU1; gluathionylation; MCU
• ISSN: 1097-4164

Ca 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 [Ca ] uptake rate, elevated mROS, and enhanced [Ca ] 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.