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Differential requirements for mitochondrial electron transport chain components in the adult murine liver

Authors :
Nicholas P Lesner
Xun Wang
Zhenkang Chen
Anderson Frank
Cameron J Menezes
Sara House
Spencer D Shelton
Andrew Lemoff
David G McFadden
Janaka Wansapura
Ralph J DeBerardinis
Prashant Mishra
Source :
eLife, Vol 11 (2022)
Publication Year :
2022
Publisher :
eLife Sciences Publications Ltd, 2022.

Abstract

Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.

Details

Language :
English
ISSN :
2050084X
Volume :
11
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.bc53e8466ccf4687be0151852c83aa36
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.80919