Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism

Claudio Bussi (), Tiaan Heunis, Enrica Pellegrino, Elliott M. Bernard, Nourdine Bah, Mariana Silva Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I. MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost and Maximiliano G. Gutierrez ()
Additional contact information
Claudio Bussi: The Francis Crick Institute
Tiaan Heunis: Newcastle University
Enrica Pellegrino: The Francis Crick Institute
Elliott M. Bernard: The Francis Crick Institute
Nourdine Bah: The Francis Crick Institute
Mariana Silva Santos: The Francis Crick Institute
Pierre Santucci: The Francis Crick Institute
Beren Aylan: The Francis Crick Institute
Angela Rodgers: The Francis Crick Institute
Antony Fearns: The Francis Crick Institute
Julia Mitschke: Albert-Ludwigs-University Freiburg
Christopher Moore: The Francis Crick Institute
James I. MacRae: The Francis Crick Institute
Maria Greco: The Francis Crick Institute
Thomas Reinheckel: Albert-Ludwigs-University Freiburg
Matthias Trost: Newcastle University
Maximiliano G. Gutierrez: The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34632-8

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