Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

Enrique Balderas; David R. Eberhardt; Sandra Lee; John M. Pleinis; Salah Sommakia; Anthony M. Balynas; Xue Yin; Mitchell C. Parker; Colin T. Maguire; Scott Cho; Marta W. Szulik; Anna Bakhtina; Ryan D. Bia; Marisa W. Friederich; Timothy M. Locke; Johan L.K. Van Hove; Stavros G. Drakos; Yasemin Sancak; Martin Tristani-Firouzi; Sarah Franklin; Aylin R. Rodan; Dipayan Chaudhuri

doi:10.1038/s41467-022-30236-4

Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

Enrique Balderas, David R. Eberhardt, Sandra Lee, John M. Pleinis, Salah Sommakia, Anthony M. Balynas, Xue Yin, Mitchell C. Parker, Colin T. Maguire, Scott Cho, Marta W. Szulik, Anna Bakhtina, Ryan D. Bia, Marisa W. Friederich, Timothy M. Locke, Johan L.K. Van Hove, Stavros G. Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah FranklinAylin R. Rodan, Dipayan Chaudhuri

Research output: Contribution to journal › Article › peer-review

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Abstract

Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.

Original language	English (US)
Article number	2769
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30236-4
State	Published - Dec 2022
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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Balderas, E., Eberhardt, D. R., Lee, S., Pleinis, J. M., Sommakia, S., Balynas, A. M., Yin, X., Parker, M. C., Maguire, C. T., Cho, S., Szulik, M. W., Bakhtina, A., Bia, R. D., Friederich, M. W., Locke, T. M., Van Hove, J. L. K., Drakos, S. G., Sancak, Y., Tristani-Firouzi, M., ... Chaudhuri, D. (2022). Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment. Nature communications, 13(1), [2769]. https://doi.org/10.1038/s41467-022-30236-4

Balderas, E, Eberhardt, DR, Lee, S, Pleinis, JM, Sommakia, S, Balynas, AM, Yin, X, Parker, MC, Maguire, CT, Cho, S, Szulik, MW, Bakhtina, A, Bia, RD, Friederich, MW, Locke, TM, Van Hove, JLK, Drakos, SG, Sancak, Y, Tristani-Firouzi, M, Franklin, S, Rodan, AR & Chaudhuri, D 2022, 'Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment', Nature communications, vol. 13, no. 1, 2769. https://doi.org/10.1038/s41467-022-30236-4

@article{5c018be48518420590a9ce84869e92bb,

title = "Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment",

abstract = "Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.",

author = "Enrique Balderas and Eberhardt, {David R.} and Sandra Lee and Pleinis, {John M.} and Salah Sommakia and Balynas, {Anthony M.} and Xue Yin and Parker, {Mitchell C.} and Maguire, {Colin T.} and Scott Cho and Szulik, {Marta W.} and Anna Bakhtina and Bia, {Ryan D.} and Friederich, {Marisa W.} and Locke, {Timothy M.} and {Van Hove}, {Johan L.K.} and Drakos, {Stavros G.} and Yasemin Sancak and Martin Tristani-Firouzi and Sarah Franklin and Rodan, {Aylin R.} and Dipayan Chaudhuri",

note = "Funding Information: We thank Edward Owusu-Ansah, Alex Whitworth, Ronald Davis, and the Bloomington Drosophila Stock Center at Indiana University (supported by NIH P40OD018537) for fly stocks, Michael Ryan for the NDUFB10, NDUFS4, and control cell lines, David Clapham for other HEK293T cell lines, John Elrod, Ronald Kahn, and Nils-G{\"o}ran Larsson for mouse lines, James Marvin and Flow Cytometry Core staff at the University of Utah (supported by NIH P30CA042014), Small Animal Ultrasound Core staff at the University of Utah, and Derek Warner and DNA Sequencing Core staff at the University of Utah. Support is from the National Institutes of Health (DK110358 [JMP, ARR], UL1TR002538 [C.T.M.], HL124070 [D.C.], HL141353 [D.C.], HL007576 [S.S.]), the Nora Eccles Treadwell Foundation (D.C., M.T.F., S.G.D., S.F.), the Gilead Sciences Research Scholars Program (D.C.), the American Heart Association Postdoctoral Fellowship Award (834544 [D.R.E.]), and the University of Utah Driving Out Diabetes, a Larry H. Miller Wellness Initiative (D.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. KO KO Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-30236-4",

language = "English (US)",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

AU - Balderas, Enrique

AU - Eberhardt, David R.

AU - Lee, Sandra

AU - Pleinis, John M.

AU - Sommakia, Salah

AU - Balynas, Anthony M.

AU - Yin, Xue

AU - Parker, Mitchell C.

AU - Maguire, Colin T.

AU - Cho, Scott

AU - Szulik, Marta W.

AU - Bakhtina, Anna

AU - Bia, Ryan D.

AU - Friederich, Marisa W.

AU - Locke, Timothy M.

AU - Van Hove, Johan L.K.

AU - Drakos, Stavros G.

AU - Sancak, Yasemin

AU - Tristani-Firouzi, Martin

AU - Franklin, Sarah

AU - Rodan, Aylin R.

AU - Chaudhuri, Dipayan

N1 - Funding Information: We thank Edward Owusu-Ansah, Alex Whitworth, Ronald Davis, and the Bloomington Drosophila Stock Center at Indiana University (supported by NIH P40OD018537) for fly stocks, Michael Ryan for the NDUFB10, NDUFS4, and control cell lines, David Clapham for other HEK293T cell lines, John Elrod, Ronald Kahn, and Nils-Göran Larsson for mouse lines, James Marvin and Flow Cytometry Core staff at the University of Utah (supported by NIH P30CA042014), Small Animal Ultrasound Core staff at the University of Utah, and Derek Warner and DNA Sequencing Core staff at the University of Utah. Support is from the National Institutes of Health (DK110358 [JMP, ARR], UL1TR002538 [C.T.M.], HL124070 [D.C.], HL141353 [D.C.], HL007576 [S.S.]), the Nora Eccles Treadwell Foundation (D.C., M.T.F., S.G.D., S.F.), the Gilead Sciences Research Scholars Program (D.C.), the American Heart Association Postdoctoral Fellowship Award (834544 [D.R.E.]), and the University of Utah Driving Out Diabetes, a Larry H. Miller Wellness Initiative (D.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. KO KO Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.

AB - Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.

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DO - 10.1038/s41467-022-30236-4

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VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

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ER -

Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

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