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.

The following data sets were generated

Article and author information

Author details

  1. Nicholas P Lesner

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Xun Wang

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Zhenkang Chen

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7919-5546
  4. Anderson Frank

    Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  5. Cameron Menezes

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5759-8099
  6. Sara House

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Spencer D Shelton

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1236-5317
  8. Andrew Lemoff

    Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4943-0170
  9. David G McFadden

    Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  10. Janaka Wanaspura

    Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  11. Ralph J DeBerardinis

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Ralph J DeBerardinis, is an advisor to Agios Pharmaceuticals.
  12. Prashant Mishra

    Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    prashant.mishra@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2223-1742

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.

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).

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Version history

  1. Preprint posted: July 15, 2021 (view preprint)
  2. Received: June 9, 2022
  3. Accepted: September 23, 2022
  4. Accepted Manuscript published: September 26, 2022 (version 1)
  5. 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.

Metrics

  • 4,019
    Page views
  • 684
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Nicholas P Lesner
  2. Xun Wang
  3. Zhenkang Chen
  4. Anderson Frank
  5. Cameron Menezes
  6. Sara House
  7. Spencer D Shelton
  8. Andrew Lemoff
  9. David G McFadden
  10. Janaka Wanaspura
  11. Ralph J DeBerardinis
  12. Prashant Mishra
(2022)
Differential requirements for mitochondrial electron transport chain components in the adult murine liver
eLife 11:e80919.
https://doi.org/10.7554/eLife.80919

Further reading

    1. Cell Biology
    2. Structural Biology and Molecular Biophysics
    Bronwyn A Lucas, Benjamin A Himes, Nikolaus Grigorieff
    Research Advance

    Previously we showed that 2D template matching (2DTM) can be used to localize macromolecular complexes in images recorded by cryogenic electron microscopy (cryo-EM) with high precision, even in the presence of noise and cellular background (Lucas et al., 2021; Lucas et al., 2022). Here, we show that once localized, these particles may be averaged together to generate high-resolution 3D reconstructions. However, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias while retaining the benefits of high-precision localization, and we show that molecular features not present in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution. Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.

    1. Cell Biology
    2. Immunology and Inflammation
    Yijun Zhang, Tao Wu ... Li Wu
    Research Article

    Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.