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Modulating mitofusins to control mitochondrial function and signaling

Author

Listed:
  • Emmanouil Zacharioudakis

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Bogos Agianian

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Vasantha Kumar MV

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Nikolaos Biris

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Thomas P. Garner

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Inna Rabinovich-Nikitin

    (University of Manitoba
    University of Manitoba
    St. Boniface Research Centre)

  • Amanda T. Ouchida

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Victoria Margulets

    (University of Manitoba
    University of Manitoba
    St. Boniface Research Centre)

  • Lars Ulrik Nordstrøm

    (Albert Einstein College of Medicine)

  • Joel S. Riley

    (Cancer Research UK Beatson Institute
    University of Glasgow)

  • Igor Dolgalev

    (New York University School of Medicine
    New York University School of Medicine
    New York University School of Medicine)

  • Yun Chen

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Andre J. H. Wittig

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Ryan Pekson

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Chris Mathew

    (Albert Einstein College of Medicine)

  • Peter Wei

    (Albert Einstein College of Medicine)

  • Aristotelis Tsirigos

    (New York University School of Medicine
    New York University School of Medicine
    New York University School of Medicine)

  • Stephen W. G. Tait

    (Cancer Research UK Beatson Institute
    University of Glasgow)

  • Lorrie A. Kirshenbaum

    (University of Manitoba
    University of Manitoba
    St. Boniface Research Centre)

  • Richard N. Kitsis

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Evripidis Gavathiotis

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

Abstract

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.

Suggested Citation

  • Emmanouil Zacharioudakis & Bogos Agianian & Vasantha Kumar MV & Nikolaos Biris & Thomas P. Garner & Inna Rabinovich-Nikitin & Amanda T. Ouchida & Victoria Margulets & Lars Ulrik Nordstrøm & Joel S. Ri, 2022. "Modulating mitofusins to control mitochondrial function and signaling," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31324-1
    DOI: 10.1038/s41467-022-31324-1
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    References listed on IDEAS

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    1. Inmaculada Martínez-Reyes & Luzivette Robles Cardona & Hyewon Kong & Karthik Vasan & Gregory S. McElroy & Marie Werner & Hermon Kihshen & Colleen R. Reczek & Samuel E. Weinberg & Peng Gao & Elizabeth , 2020. "Mitochondrial ubiquinol oxidation is necessary for tumour growth," Nature, Nature, vol. 585(7824), pages 288-292, September.
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    3. Xiomaris M. Cotto-Rios & Bogos Agianian & Nadege Gitego & Emmanouil Zacharioudakis & Orsi Giricz & Yang Wu & Yiyu Zou & Amit Verma & Poulikos I. Poulikakos & Evripidis Gavathiotis, 2020. "Inhibitors of BRAF dimers using an allosteric site," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    4. Yu-Jie Li & Yu-Lu Cao & Jian-Xiong Feng & Yuanbo Qi & Shuxia Meng & Jie-Feng Yang & Ya-Ting Zhong & Sisi Kang & Xiaoxue Chen & Lan Lan & Li Luo & Bing Yu & Shoudeng Chen & David C. Chan & Junjie Hu & , 2019. "Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    5. Antonietta Franco & Richard N. Kitsis & Julie A. Fleischer & Evripidis Gavathiotis & Opher S. Kornfeld & Guohua Gong & Nikolaos Biris & Ann Benz & Nir Qvit & Sara K. Donnelly & Yun Chen & Steven Menne, 2016. "Correcting mitochondrial fusion by manipulating mitofusin conformations," Nature, Nature, vol. 540(7631), pages 74-79, December.
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    Cited by:

    1. Vanessa López-Polo & Mate Maus & Emmanouil Zacharioudakis & Miguel Lafarga & Camille Stephan-Otto Attolini & Francisco D. M. Marques & Marta Kovatcheva & Evripidis Gavathiotis & Manuel Serrano, 2024. "Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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