Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

Elife. 2019 Dec 3;8:e51031. doi: 10.7554/eLife.51031.

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.

Keywords: acidification; brain; cell biology; human; human biology; inflammation; iron; lysosome; medicine; mitochondria; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism*
  • Animals
  • Apoptosis
  • Brain / metabolism
  • Cell Hypoxia / drug effects
  • Cell Proliferation
  • DNA, Mitochondrial / genetics
  • Disease Models, Animal
  • Electron Transport
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Homeostasis
  • Hydrogen-Ion Concentration
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunity, Innate
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Iron / deficiency*
  • Iron / pharmacology
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Organelle Biogenesis
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors
  • Vacuolar Proton-Translocating ATPases / metabolism
  • alpha-Glucosidases / deficiency
  • alpha-Glucosidases / metabolism

Substances

  • Acids
  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Iron
  • alpha-Glucosidases
  • Vacuolar Proton-Translocating ATPases

Associated data

  • GEO/GSE134704
  • GEO/GSE16870
  • GEO/GSE47836
  • GEO/GSE60570