Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo.
King Faisal YambireChristine RostoskyTakashi WatanabeDavid Pacheu-GrauSylvia Torres-OdioAngela Sanchez-GuerreroOla SenderovichEsther G Meyron-HoltzIra MilosevicJens FrahmA Phillip WestNuno RaimundoPublished in: eLife (2019)
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.
Keyphrases
- iron deficiency
- mitochondrial dna
- oxidative stress
- cell death
- magnetic resonance imaging
- copy number
- mouse model
- induced apoptosis
- cell cycle arrest
- machine learning
- computed tomography
- dna methylation
- type diabetes
- weight loss
- spinal cord
- white matter
- spinal cord injury
- gene expression
- signaling pathway
- contrast enhanced
- resting state
- functional connectivity
- diffusion weighted imaging
- wild type