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Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics

Author

Listed:
  • William A. Hofstadter

    (Princeton University)

  • Katelyn C. Cook

    (Princeton University)

  • Elene Tsopurashvili

    (Princeton University)

  • Robert Gebauer

    (Universität Hamburg
    Centre for Structural Systems Biology, Leibniz Institute of Virology)

  • Vojtěch Pražák

    (Universität Hamburg
    Centre for Structural Systems Biology, Leibniz Institute of Virology)

  • Emily A. Machala

    (Universität Hamburg
    Centre for Structural Systems Biology, Leibniz Institute of Virology)

  • Ji Woo Park

    (Princeton University)

  • Kay Grünewald

    (Universität Hamburg
    Centre for Structural Systems Biology, Leibniz Institute of Virology)

  • Emmanuelle R. J. Quemin

    (Universität Hamburg
    Centre for Structural Systems Biology, Leibniz Institute of Virology
    Institute for Integrative Biology of the Cell, CNRS UMR9198)

  • Ileana M. Cristea

    (Princeton University)

Abstract

The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.

Suggested Citation

  • William A. Hofstadter & Katelyn C. Cook & Elene Tsopurashvili & Robert Gebauer & Vojtěch Pražák & Emily A. Machala & Ji Woo Park & Kay Grünewald & Emmanuelle R. J. Quemin & Ileana M. Cristea, 2024. "Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51680-4
    DOI: 10.1038/s41467-024-51680-4
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    References listed on IDEAS

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    1. Martin Picard & Meagan J. McManus & György Csordás & Péter Várnai & Gerald W. Dorn II & Dewight Williams & György Hajnóczky & Douglas C. Wallace, 2015. "Trans-mitochondrial coordination of cristae at regulated membrane junctions," Nature Communications, Nature, vol. 6(1), pages 1-8, May.
    2. Atsushi Hoshino & Wei-jia Wang & Shogo Wada & Chris McDermott-Roe & Chantell S. Evans & Bridget Gosis & Michael P. Morley & Komal S. Rathi & Jian Li & Kristina Li & Steven Yang & Meagan J. McManus & C, 2019. "The ADP/ATP translocase drives mitophagy independent of nucleotide exchange," Nature, Nature, vol. 575(7782), pages 375-379, November.
    3. Yuki Hanada & Naotada Ishihara & Lixiang Wang & Hidenori Otera & Takaya Ishihara & Takumi Koshiba & Katsuyoshi Mihara & Yoshihiro Ogawa & Masatoshi Nomura, 2020. "MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
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