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.

Reviewing Editor

  1. 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

  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

  • 4,668
    views
  • 769
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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

Share this article

https://doi.org/10.7554/eLife.80919

Further reading

    1. Cell Biology
    Yi-Ju Chen, Shun-Cheng Tseng ... Eric Hwang
    Research Article

    A functional nervous system is built upon the proper morphogenesis of neurons to establish the intricate connection between them. The microtubule cytoskeleton is known to play various essential roles in this morphogenetic process. While many microtubule-associated proteins (MAPs) have been demonstrated to participate in neuronal morphogenesis, the function of many more remains to be determined. This study focuses on a MAP called HMMR in mice, which was originally identified as a hyaluronan binding protein and later found to possess microtubule and centrosome binding capacity. HMMR exhibits high abundance on neuronal microtubules and altering the level of HMMR significantly affects the morphology of neurons. Instead of confining to the centrosome(s) like cells in mitosis, HMMR localizes to microtubules along axons and dendrites. Furthermore, transiently expressing HMMR enhances the stability of neuronal microtubules and increases the formation frequency of growing microtubules along the neurites. HMMR regulates the microtubule localization of a non-centrosomal microtubule nucleator TPX2 along the neurite, offering an explanation for how HMMR contributes to the promotion of growing microtubules. This study sheds light on how cells utilize proteins involved in mitosis for non-mitotic functions.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Jiabin Pan, Rui Zhou ... Xiang-dong Li
    Research Article

    Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, that is, the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.