2. Academic Validation
  3. Modulating mitofusins to control mitochondrial function and signaling

Modulating mitofusins to control mitochondrial function and signaling

  • Nat Commun. 2022 Jul 7;13(1):3775. doi: 10.1038/s41467-022-31324-1.
Emmanouil Zacharioudakis 1 2 3 4 5,  Bogos Agianian 1 2 3 4 5,  Vasantha Kumar Mv 1 2 3 4 5,  Nikolaos Biris 1 2 3 4 5,  Thomas P Garner 1 2 3 4 5,  Inna Rabinovich-Nikitin 6 7 8,  Amanda T Ouchida 1 2 3 4 5,  Victoria Margulets 6 7 8,  Lars Ulrik Nordstrøm 1,  Joel S Riley 9 10,  Igor Dolgalev 11 12 13,  Yun Chen 2 3 4 14 15,  Andre J H Wittig 2 3 4 14 15,  Ryan Pekson 2 3 4 14 15,  Chris Mathew 1,  Peter Wei 1,  Aristotelis Tsirigos 11 12 13,  Stephen W G Tait 9 10,  Lorrie A Kirshenbaum 6 7 8,  Richard N Kitsis 2 3 4 14 15,  Evripidis Gavathiotis 16 17 18 19 20
Affiliations

Affiliations

  • 1 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 2 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 3 Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 4 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 5 Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 6 Department of Physiology and Pathophysiology, Max Rady College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
  • 7 Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
  • 8 Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, MB, Canada.
  • 9 Cancer Research UK Beatson Institute, Glasgow, UK.
  • 10 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 11 Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • 12 Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
  • 13 Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY, USA.
  • 14 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 15 Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 16 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 17 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 18 Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 19 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 20 Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
PMID: 35798717 DOI: 10.1038/s41467-022-31324-1
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.

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