Iron status influences mitochondrial disease progression in Complex I-deficient mice
- University of Washington, United States
- University of Cincinnati, United States
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).
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Data from: Iron Status Influences Mitochondrial Disease Progression in Complex I-Deficient MiceDryad Digital Repository, doi:10.5061/dryad.xpnvx0khb.
Article and author information
Author details
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.
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.
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.
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Iron status influences mitochondrial disease progression in Complex I-deficient mice
eLife 12:e75825.
https://doi.org/10.7554/eLife.75825
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