Article ; Online: Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
2022 Volume 13, Issue 1, Page(s) 2769
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. ... ...
| 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. |
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| MeSH term(s) | Animals ; Calcium/metabolism ; Calcium Channels/metabolism ; Homeostasis ; Mitochondria/metabolism |
| Chemical Substances | Calcium Channels ; mitochondrial calcium uniporter ; Calcium (SY7Q814VUP) |
| Language | English |
| Publishing date | 2022-05-19 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-022-30236-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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