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

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, Kaamashri Mangar, Navneet Narula, Stuart D. Katz, Boyan Zhou, Huilin Li, Aleksandr B. Stotland, Roberta A. Gottlieb, Ann Marie Schmidt, Alexander Shekhtman and Ravichandran Ramasamy ()
Additional contact information
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

Nature Communications, 2023, vol. 14, issue 1, 1-25

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42521-x

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