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 language | English (US) |
|---|---|
| Pages (from-to) | 1014-1028.e7 |
| Journal | Molecular cell |
| Volume | 65 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 16 2017 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology
Cite this
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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.
In: Molecular cell, Vol. 65, No. 6, 16.03.2017, p. 1014-1028.e7.Research output: Contribution to journal › Article
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
Y1 - 2017/3/16
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.
UR - http://www.scopus.com/inward/record.url?scp=85014115995&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014115995&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2017.01.032
DO - 10.1016/j.molcel.2017.01.032
M3 - Article
C2 - 28262504
AN - SCOPUS:85014115995
VL - 65
SP - 1014-1028.e7
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -