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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.

Original publication

DOI

10.7554/elife.51031

Type

Journal article

Journal

eLife

Publication Date

03/12/2019

Volume

8

Addresses

Institute of Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany.

Keywords

Brain, Lysosomes, Mitochondria, Animals, Mice, Disease Models, Animal, Inflammation, Acids, Iron, Vacuolar Proton-Translocating ATPases, alpha-Glucosidases, DNA, Mitochondrial, Enzyme Inhibitors, Apoptosis, Cell Proliferation, Cell Hypoxia, Gene Expression Regulation, Electron Transport, Homeostasis, Hydrogen-Ion Concentration, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Innate, Organelle Biogenesis, Iron Deficiencies