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DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Author

Listed:
  • Gautham Yepuri

    (NYU Grossman School of Medicine)

  • Lisa M. Ramirez

    (University of Albany, State University of New York)

  • Gregory G. Theophall

    (University of Albany, State University of New York)

  • Sergei V. Reverdatto

    (University of Albany, State University of New York)

  • Nosirudeen Quadri

    (NYU Grossman School of Medicine)

  • Syed Nurul Hasan

    (NYU Grossman School of Medicine)

  • Lei Bu

    (NYU Grossman School of Medicine)

  • Devi Thiagarajan

    (NYU Grossman School of Medicine)

  • Robin Wilson

    (NYU Grossman School of Medicine)

  • Raquel López Díez

    (NYU Grossman School of Medicine)

  • Paul F. Gugger

    (NYU Grossman School of Medicine)

  • Kaamashri Mangar

    (NYU Grossman School of Medicine)

  • Navneet Narula

    (NYU Grossman School of Medicine)

  • Stuart D. Katz

    (NYU Grossman School of Medicine)

  • Boyan Zhou

    (NYU Grossman School of Medicine)

  • Huilin Li

    (NYU Grossman School of Medicine)

  • Aleksandr B. Stotland

    (Smidt Heart Institute, Cedars-Sinai Medical Center)

  • Roberta A. Gottlieb

    (Smidt Heart Institute, Cedars-Sinai Medical Center)

  • Ann Marie Schmidt

    (NYU Grossman School of Medicine)

  • Alexander Shekhtman

    (University of Albany, State University of New York)

  • Ravichandran Ramasamy

    (NYU Grossman School of Medicine)

Abstract

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

Suggested Citation

  • Gautham Yepuri & Lisa M. Ramirez & Gregory G. Theophall & Sergei V. Reverdatto & Nosirudeen Quadri & Syed Nurul Hasan & Lei Bu & Devi Thiagarajan & Robin Wilson & Raquel López Díez & Paul F. Gugger & , 2023. "DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42521-x
    DOI: 10.1038/s41467-023-42521-x
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    References listed on IDEAS

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    1. 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.
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    1. Lorrie A. Kirshenbaum & Rimpy Dhingra & Roberto Bravo-Sagua & Sergio Lavandero, 2024. "DIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia," Nature Communications, Nature, vol. 15(1), pages 1-3, December.

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