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

57 Citations (Scopus)

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

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Oxidation-Reduction
Cysteine
Sulfhydryl Compounds
Energy Metabolism
Signal Transduction
Cell Death
Mutation
Hypoxia

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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. / Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity. In: Molecular cell. 2017 ; Vol. 65, No. 6. pp. 1014-1028.e7.
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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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Dong, Z, Shanmughapriya, S, Tomar, D, Siddiqui, N, Lynch, S, Nemani, N, Breves, SL, Zhang, X, Tripathi, A, Palaniappan, P, Riitano, MF, Worth, AM, Seelam, A, Carvalho, E, Subbiah, R, Jaña, F, Soboloff, J, Peng, Y, Cheung, JY, Joseph, SK, Caplan, J, Rajan, S, Stathopulos, PB & Madesh, M 2017, 'Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity', Molecular cell, vol. 65, no. 6, pp. 1014-1028.e7. https://doi.org/10.1016/j.molcel.2017.01.032

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.

In: Molecular cell, Vol. 65, No. 6, 16.03.2017, p. 1014-1028.e7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

AU - Dong, Zhiwei

AU - Shanmughapriya, Santhanam

AU - Tomar, Dhanendra

AU - Siddiqui, Naveed

AU - Lynch, Solomon

AU - Nemani, Neeharika

AU - Breves, Sarah L.

AU - Zhang, Xueqian

AU - Tripathi, Aparna

AU - Palaniappan, Palaniappan

AU - Riitano, Massimo F.

AU - Worth, Alison M.

AU - Seelam, Ajay

AU - Carvalho, Edmund

AU - Subbiah, Ramasamy

AU - Jaña, Fabián

AU - Soboloff, Jonathan

AU - Peng, Yizhi

AU - Cheung, Joseph Y.

AU - Joseph, Suresh K.

AU - Caplan, Jeffrey

AU - Rajan, Sudarsan

AU - Stathopulos, Peter B.

AU - Madesh, Muniswamy

PY - 2017/3/16

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N2 - 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.

AB - 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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