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The Mechanism of MICU-Dependent Gating of the Mitochondrial Ca2+ Uniporter

Vivek Garg, Ishan Paranjpe, Tiffany Unsulangi, Junji Suzuki, Lorin S. Milescu, Yuriy Kirichok
doi: https://doi.org/10.1101/2020.04.04.025833
Vivek Garg
1Department of Physiology, University of California San Francisco, San Francisco, CA, USA
2Department of Physiology, University of Maryland, Baltimore, MD, USA
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  • For correspondence: yuriy.kirichok@ucsf.edu vgarg@som.umaryland.edu
Ishan Paranjpe
1Department of Physiology, University of California San Francisco, San Francisco, CA, USA
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Tiffany Unsulangi
1Department of Physiology, University of California San Francisco, San Francisco, CA, USA
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Junji Suzuki
1Department of Physiology, University of California San Francisco, San Francisco, CA, USA
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Lorin S. Milescu
3Department of Biology, University of Maryland, College Park, MD, USA
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Yuriy Kirichok
1Department of Physiology, University of California San Francisco, San Francisco, CA, USA
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  • For correspondence: yuriy.kirichok@ucsf.edu vgarg@som.umaryland.edu
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Abstract

Mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ uptake, regulating ATP production and cell death. According to the existing paradigm, MCU is occluded at the resting cytosolic [Ca2+] and only opens above an ∼400 nM threshold. This Ca2+-dependent gating is putatively conferred by MICUs, EF hand-containing auxiliary subunits that block/unblock the MCU pore depending on cytosolic [Ca2+]. Here we provide the first direct, patch-clamp based analysis of the Ca2+-dependent MCU gating and the role played by MICUs. Surprisingly, MICUs do not occlude the MCU pore, and MCU is a constitutively active channel without cytosolic [Ca2+] activation threshold. Instead, MICUs potentiate MCU activity when cytosolic Ca2+ binds to their EF hands. MICUs cause this potentiation by increasing the probability of open state of the MCU channel.

One Sentence Summary Auxiliary MICU subunits do not occlude the mitochondrial Ca2+ uniporter (MCU) but increase its activity as cytosolic Ca2+ is elevated.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This version of the manuscript has the updated citation list.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 29, 2020.
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The Mechanism of MICU-Dependent Gating of the Mitochondrial Ca2+ Uniporter
Vivek Garg, Ishan Paranjpe, Tiffany Unsulangi, Junji Suzuki, Lorin S. Milescu, Yuriy Kirichok
bioRxiv 2020.04.04.025833; doi: https://doi.org/10.1101/2020.04.04.025833
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The Mechanism of MICU-Dependent Gating of the Mitochondrial Ca2+ Uniporter
Vivek Garg, Ishan Paranjpe, Tiffany Unsulangi, Junji Suzuki, Lorin S. Milescu, Yuriy Kirichok
bioRxiv 2020.04.04.025833; doi: https://doi.org/10.1101/2020.04.04.025833

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