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Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism

Author

Listed:
  • Claudio Bussi

    (The Francis Crick Institute)

  • Tiaan Heunis

    (Newcastle University
    University of Oxford)

  • Enrica Pellegrino

    (The Francis Crick Institute)

  • Elliott M. Bernard

    (The Francis Crick Institute
    University of Lausanne)

  • Nourdine Bah

    (The Francis Crick Institute)

  • Mariana Silva Santos

    (The Francis Crick Institute)

  • Pierre Santucci

    (The Francis Crick Institute
    Aix-Marseille Univ, CNRS, LISM, IMM FR3479)

  • Beren Aylan

    (The Francis Crick Institute)

  • Angela Rodgers

    (The Francis Crick Institute)

  • Antony Fearns

    (The Francis Crick Institute)

  • Julia Mitschke

    (Albert-Ludwigs-University Freiburg
    German Cancer Research Center (DKFZ))

  • Christopher Moore

    (The Francis Crick Institute)

  • James I. MacRae

    (The Francis Crick Institute)

  • Maria Greco

    (The Francis Crick Institute
    University of Oxford)

  • Thomas Reinheckel

    (Albert-Ludwigs-University Freiburg
    German Cancer Research Center (DKFZ)
    Albert-Ludwigs-University Freiburg)

  • Matthias Trost

    (Newcastle University)

  • Maximiliano G. Gutierrez

    (The Francis Crick Institute)

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.

Suggested Citation

  • Claudio Bussi & Tiaan Heunis & Enrica Pellegrino & Elliott M. Bernard & Nourdine Bah & Mariana Silva Santos & Pierre Santucci & Beren Aylan & Angela Rodgers & Antony Fearns & Julia Mitschke & Christop, 2022. "Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34632-8
    DOI: 10.1038/s41467-022-34632-8
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    References listed on IDEAS

    as
    1. Thomas MacVicar & Yohsuke Ohba & Hendrik Nolte & Fiona Carola Mayer & Takashi Tatsuta & Hans-Georg Sprenger & Barbara Lindner & Yue Zhao & Jiahui Li & Christiane Bruns & Marcus Krüger & Markus Habich , 2019. "Lipid signalling drives proteolytic rewiring of mitochondria by YME1L," Nature, Nature, vol. 575(7782), pages 361-365, November.
    2. Saara Hämälistö & Jonathan Lucien Stahl & Elena Favaro & Qing Yang & Bin Liu & Line Christoffersen & Ben Loos & Claudia Guasch Boldú & Johanna A. Joyce & Thomas Reinheckel & Marin Barisic & Marja Jäät, 2020. "Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Yvette C. Wong & Daniel Ysselstein & Dimitri Krainc, 2018. "Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis," Nature, Nature, vol. 554(7692), pages 382-386, February.
    4. Hideaki Morishita & Tomoya Eguchi & Satoshi Tsukamoto & Yuriko Sakamaki & Satoru Takahashi & Chieko Saito & Ikuko Koyama-Honda & Noboru Mizushima, 2021. "Organelle degradation in the lens by PLAAT phospholipases," Nature, Nature, vol. 592(7855), pages 634-638, April.
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