Differential requirements for mitochondrial electron transport chain components in the adult murine liver
- The University of Texas Southwestern Medical Center, United States
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.
Data availability
Data and material availability: Proteomics datasets have been deposited into the PRIDE database (identifier PXD031716), and metabolomics datasets have been deposited into Metabolomics Workbench (identifiers 3426, 3428, 3429). All other data are provided within the manuscript and supplementary files.
Article and author information
Author details
Funding
United Mitochondrial Disease Foundation
- Prashant Mishra
National Institutes of Health (1DP2ES030449-01)
- Prashant Mishra
National Institutes of Health (1R01AR073217-01)
- Prashant Mishra
National Institutes of Health (1F31-DK122676)
- Nicholas P Lesner
Moody Medical Research Institute
- Prashant Mishra
National Science Foundation (GRFP 2019281210)
- Spencer D Shelton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Agnieszka Chacinska, University of Warsaw, Poland
Ethics
Animal experimentation: All mouse experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) at University of Texas Southwestern Medical Center (protocol 102654).
Version history
- Preprint posted: July 15, 2021 (view preprint)
- Received: June 9, 2022
- Accepted: September 23, 2022
- Accepted Manuscript published: September 26, 2022 (version 1)
- Version of Record published: November 10, 2022 (version 2)
Copyright
© 2022, Lesner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Differential requirements for mitochondrial electron transport chain components in the adult murine liver
eLife 11:e80919.
https://doi.org/10.7554/eLife.80919
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