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.
We generated RNAseq data from brain of mice (WT and KO), which is deposited in Gene Expression Omnibus under the serial number Series GSE134704.
Cortical transcriptome reveals widespread inflammation in brain of Gaa-/- miceNCBI Gene Expression Omnibus, GSE134704.
HeLa cells treated with V-ATPase inhibitors or with desoxyferramine compared to HeLa in DMSO or medium with low LDLNCBI Gene Expression Omnibus, GSE16870.
Human colon carcinoma cell line treated with bafilomycin A1NCBI Gene Expression Omnibus, GSE47836.
Aneuploidy-induced cellular stresses limit autophagic degradation.NCBI Gene Expression Omnibus, GSE60570.
- Nuno Raimundo
- 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.
Animal experimentation: The experiments were performed under the permit 15-883 by the authority for animal research in Lower Saxony, Germany (LAVES).
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
© 2019, Yambire et al.
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