Abstract

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin, and show changes in iron responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files or are publicly available via Dryad (https://doi.org/10.5061/dryad.xpnvx0khb).

The following data sets were generated

Article and author information

Author details

  1. CJ Kelly

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Reid K Couch

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Vivian T Ha

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Camille M Bodart

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Judy Wu

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sydney Huff

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicole T Herrel

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hyunsung D Kim

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Azaad O Zimmermann

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jessica Shattuck

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yu-Chen Pan

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Matt Kaeberlein

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
    For correspondence
    kaeber@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1311-3421
  13. Anthony S Grillo

    Department of Chemistry, University of Cincinnati, Seattle, United States
    For correspondence
    grilloas@uc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3283-6585

Funding

National Institutes of Health (F32 NS110109)

  • Anthony S Grillo

National Institutes of Health (R01 NS098329)

  • Matt Kaeberlein

National Institutes of Health (P30 AG013280)

  • Matt Kaeberlein

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yvette Yien

Ethics

Animal experimentation: Experiments, procedures, and protocols described herein to care for, and handle, mice were reviewed and approved (protocol 4359-03) by the University of Washington Institutional Animal Care and Use Committee (IACUC) and strictly adhered to guidelines described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

Version history

  1. Preprint posted: September 29, 2021 (view preprint)
  2. Received: November 24, 2021
  3. Accepted: February 10, 2023
  4. Accepted Manuscript published: February 17, 2023 (version 1)
  5. Version of Record published: March 21, 2023 (version 2)

Copyright

© 2023, Kelly 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

  • 2,292
    Page views
  • 308
    Downloads
  • 5
    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. CJ Kelly
  2. Reid K Couch
  3. Vivian T Ha
  4. Camille M Bodart
  5. Judy Wu
  6. Sydney Huff
  7. Nicole T Herrel
  8. Hyunsung D Kim
  9. Azaad O Zimmermann
  10. Jessica Shattuck
  11. Yu-Chen Pan
  12. Matt Kaeberlein
  13. Anthony S Grillo
(2023)
Iron status influences mitochondrial disease progression in Complex I-deficient mice
eLife 12:e75825.
https://doi.org/10.7554/eLife.75825

Share this article

https://doi.org/10.7554/eLife.75825

Further reading

    1. Biochemistry and Chemical Biology
    Valentin Bohl, Nele Merret Hollmann ... Axel Mogk
    Research Article

    Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during, e.g., food processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL from Listeria monocytogenes that provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Tien M Phan, Young C Kim ... Jeetain Mittal
    Research Article

    The heterochromatin protein 1 (HP1) family is a crucial component of heterochromatin with diverse functions in gene regulation, cell cycle control, and cell differentiation. In humans, there are three paralogs, HP1α, HP1β, and HP1γ, which exhibit remarkable similarities in their domain architecture and sequence properties. Nevertheless, these paralogs display distinct behaviors in liquid-liquid phase separation (LLPS), a process linked to heterochromatin formation. Here, we employ a coarse-grained simulation framework to uncover the sequence features responsible for the observed differences in LLPS. We highlight the significance of the net charge and charge patterning along the sequence in governing paralog LLPS propensities. We also show that both highly conserved folded and less-conserved disordered domains contribute to the observed differences. Furthermore, we explore the potential co-localization of different HP1 paralogs in multicomponent assemblies and the impact of DNA on this process. Importantly, our study reveals that DNA can significantly reshape the stability of a minimal condensate formed by HP1 paralogs due to competitive interactions of HP1α with HP1β and HP1γ versus DNA. In conclusion, our work highlights the physicochemical nature of interactions that govern the distinct phase-separation behaviors of HP1 paralogs and provides a molecular framework for understanding their role in chromatin organization.