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 - 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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U2 - 10.1038/s41467-022-30236-4
DO - 10.1038/s41467-022-30236-4
M3 - Article
C2 - 35589699
AN - SCOPUS:85130312063
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2769
ER -