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. Hove, Stavros G. Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R. Rodan and Dipayan Chaudhuri ()
Additional contact information
Enrique Balderas: University of Utah
David R. Eberhardt: University of Utah
Sandra Lee: University of Utah
John M. Pleinis: University of Utah
Salah Sommakia: University of Utah
Anthony M. Balynas: University of Utah
Xue Yin: University of Utah
Mitchell C. Parker: University of Nevada Reno School of Medicine
Colin T. Maguire: University of Utah
Scott Cho: University of Utah
Marta W. Szulik: University of Utah
Anna Bakhtina: University of Utah
Ryan D. Bia: University of Utah
Marisa W. Friederich: University of Colorado
Timothy M. Locke: University of Washington
Johan L. K. Hove: University of Colorado
Stavros G. Drakos: University of Utah
Yasemin Sancak: University of Washington
Martin Tristani-Firouzi: University of Utah
Sarah Franklin: University of Utah
Aylin R. Rodan: University of Utah
Dipayan Chaudhuri: University of Utah

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30236-4

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