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  Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo.

Yambire, K. F., Rostosky, C., Watanabe, T., Pacheu-Grau, D., Torres-Odio, S., Sanchez-Guerrero, A., et al. (2019). Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife, 8: e51031. doi:10.7554/eLife.51031.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-5576-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-BD9B-8
Genre: Journal Article

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 Creators:
Yambire, K. F., Author
Rostosky, C., Author
Watanabe, T.1, Author              
Pacheu-Grau, D., Author
Torres-Odio, S., Author
Sanchez-Guerrero, A., Author
Senderovich, O., Author
Meyron-Holtz, E. G., Author
Milosevic, I., Author
Frahm, J.1, Author              
West, A. P., Author
Raimundo, N., Author
Affiliations:
1Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society, ou_578634              

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Free keywords: cell biology; human; human biology; medicine; mouse
 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.

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Language(s): eng - English
 Dates: 2019-12-03
 Publication Status: Published online
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.7554/eLife.51031
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Title: eLife
Source Genre: Journal
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Pages: 36 Volume / Issue: 8 Sequence Number: e51031 Start / End Page: - Identifier: -