Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism
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Claudio Bussi Tiaan Heunis Enrica Pellegrino Elliott Bernard Nourdine Bah Mariana Silva Dos Santos Pierre Santucci Beren Aylan Angela Rodgers Tony Fearns Julia Mitschke Christopher Moore James Macrae Maria Greco Thomas Reinheckel Matthias Trost Maximiliano GutierrezAbstract
Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
Journal details
Journal Nature Communications
Volume 13
Issue number 1
Pages 7338
Available online
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Publisher website (DOI) 10.1038/s41467-022-34632-8
Europe PubMed Central 36443305
Pubmed 36443305
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