IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34632-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34632-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-34632-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Zoë P. Van Acker & Anika Perdok & Ruben Hellemans & Katherine North & Inge Vorsters & Cedric Cappel & Jonas Dehairs & Johannes V. Swinnen & Ragna Sannerud & Marine Bretou & Markus Damme & Wim Annaert, 2023. "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Satoshi Watanabe & Yuta Nihongaki & Kie Itoh & Toru Uyama & Satoshi Toda & Shigeki Watanabe & Takanari Inoue, 2022. "Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Ryouhei Tsutsumi & Beatrix Ueberheide & Feng-Xia Liang & Benjamin G. Neel & Ryuichi Sakai & Yoshiro Saito, 2024. "Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Jasjot Singh & Hadeer Elhabashy & Pathma Muthukottiappan & Markus Stepath & Martin Eisenacher & Oliver Kohlbacher & Volkmar Gieselmann & Dominic Winter, 2022. "Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Kangqiang Qiu & Weiwei Zou & Hongbao Fang & Mingang Hao & Kritika Mehta & Zhiqi Tian & Jun-Lin Guan & Kai Zhang & Taosheng Huang & Jiajie Diao, 2022. "Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    6. Gong-Her Wu & Charlene Smith-Geater & Jesús G. Galaz-Montoya & Yingli Gu & Sanket R. Gupte & Ranen Aviner & Patrick G. Mitchell & Joy Hsu & Ricardo Miramontes & Keona Q. Wang & Nicolette R. Geller & C, 2023. "CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    7. George K. E. Umanah & Leire Abalde-Atristain & Mohammed Repon Khan & Jaba Mitra & Mohamad Aasif Dar & Melissa Chang & Kavya Tangella & Amy McNamara & Samuel Bennett & Rong Chen & Vasudha Aggarwal & Ma, 2022. "AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Jiamin Qiu & Feng Yue & Peipei Zhu & Jingjuan Chen & Fan Xu & Lijia Zhang & Kun Ho Kim & Madigan M. Snyder & Nanjian Luo & Hao-wei Xu & Fang Huang & W. Andy Tao & Shihuan Kuang, 2023. "FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34632-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.