TY - JOUR
T1 - Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo
AU - Yambire, King Faisal
AU - Rostosky, Christine
AU - Watanabe, Takashi
AU - Pacheu-Grau, David
AU - Torres-Odio, Sylvia
AU - Sanchez-Guerrero, Angela
AU - Senderovich, Ola
AU - Meyron-Holtz, Esther G.
AU - Milosevic, Ira
AU - Frahm, Jens
AU - Phillip West, A.
AU - Raimundo, Nuno
N1 - Funding Information:
1Institute of Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany; 2European Neuroscience Institute, a Joint Initiative of the Max-Planck Institute and of the University Medical Center Goettingen, Goettingen, Germany; 3Biomedizinische NMR, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany; 4Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Austin, United States; 5Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel
Funding Information:
This work was supported by a Starting Grant from the European Research Council (337327, MitoPex-Lyso), to NR. This project stems from results obtained under the support of a research grant from the Acid Maltase Deficiency Association (to NR). IM lab was supported by a Emmy Noether award from the Deutsche Forschungsgemeinschaft (DFG). NR and IM were supported by the Collaborative Research Center SFB1190-P02 by DFG.
Funding Information:
This work was supported by a Starting Grant from the European Research Council (337327, MitoPex-Lyso), to NR. This project stems from results obtained under the support of a research grant from the Acid Maltase Deficiency Association (to NR). IM lab was supported by a Emmy Noether award from the Deutsche Forschungsgemeinschaft (DFG). NR and IM were supported by the Collaborative Research Center SFB1190-P02 by DFG. The authors thank the technical support of Dirk Schwitters, and thank Adrian M Raimundo for discussions on the project. We thank Prof. D?rthe Katschinski (Universit?tsmedizin G?ttingen) for the primers to test HIF targets, and Prof. David Sabatini for the Addgene construct 102930.
Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.51031
DO - 10.7554/eLife.51031
M3 - Article
C2 - 31793879
AN - SCOPUS:85076874631
VL - 8
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e51031
ER -