Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

Zhiwei Dong, Santhanam Shanmughapriya, Dhanendra Tomar, Naveed Siddiqui, Solomon Lynch, Neeharika Nemani, Sarah L. Breves, Xueqian Zhang, Aparna Tripathi, Palaniappan Palaniappan, Massimo F. Riitano, Alison M. Worth, Ajay Seelam, Edmund Carvalho, Ramasamy Subbiah, Fabián Jaña, Jonathan Soboloff, Yizhi Peng, Joseph Y. Cheung, Suresh K. JosephJeffrey Caplan, Sudarsan Rajan, Peter B. Stathopulos, Muniswamy Madesh

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1014-1028.e7
JournalMolecular cell
Volume65
Issue number6
DOIs
StatePublished - Mar 16 2017

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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