Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

King Faisal Yambire, Christine Rostosky, Takashi Watanabe, David Pacheu-Grau, Sylvia Torres-Odio, Angela Sanchez-Guerrero, Ola Senderovich, Esther G. Meyron-Holtz, Ira Milosevic, Jens Frahm, A. Phillip West, Nuno Raimundo

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Article numbere51031
JournaleLife
Volume8
DOIs
StatePublished - Dec 2019

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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