Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo
- University Medical Center Göttingen, Germany
- European Neuroscience Institute, Germany
- Max-Planck Institute for Biophysical Chemistry, Germany
- Texas A&M University Health Science Center, United States
- Technion Israel Institute of Technology, Israel
Abstract
Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.
Data availability
We generated RNAseq data from brain of mice (WT and KO), which is deposited in Gene Expression Omnibus under the serial number Series GSE134704.
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Cortical transcriptome reveals widespread inflammation in brain of Gaa-/- miceNCBI Gene Expression Omnibus, GSE134704.
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Human colon carcinoma cell line treated with bafilomycin A1NCBI Gene Expression Omnibus, GSE47836.
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Aneuploidy-induced cellular stresses limit autophagic degradation.NCBI Gene Expression Omnibus, GSE60570.
Article and author information
Author details
Funding
H2020 European Research Council (337327)
- Nuno Raimundo
Deutsche Forschungsgemeinschaft (SFB1190-P02)
- Ira Milosevic
- Nuno Raimundo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
Ethics
Animal experimentation: The experiments were performed under the permit 15-883 by the authority for animal research in Lower Saxony, Germany (LAVES).
Version history
- Received: August 12, 2019
- Accepted: December 2, 2019
- Accepted Manuscript published: December 3, 2019 (version 1)
- Version of Record published: December 17, 2019 (version 2)
Copyright
© 2019, Yambire 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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Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo
eLife 8:e51031.
https://doi.org/10.7554/eLife.51031
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