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Modulating mitofusins to control mitochondrial function and signaling

Emmanouil Zacharioudakis1,2,3,4,5, Bogos Agianian1,2,3,4,5, Vasantha Kumar Mv1,2,3,4,5

  • 1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.

Nature Communications
|July 7, 2022
PubMed

Insights

Small molecules modulate mitofusins, proteins regulating mitochondrial fusion. Activating mitofusins enhances mitochondrial function, while inhibition triggers DNA damage and potentiates apoptosis.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Mitofusins are key regulators of mitochondrial fusion, located on the outer mitochondrial membrane.
  • Mitochondrial fusion is crucial for various cellular processes and is controlled by mitofusin conformational changes and oligomerization.

Purpose of the Study:

  • To identify small molecules that modulate mitofusin activity.
  • To investigate the role of mitofusin activity in mitochondrial fusion, function, and signaling.
  • To elucidate the downstream effects of mitofusin modulation.

Main Methods:

  • Screening for small molecules that directly affect mitofusin conformation and oligomerization.
  • Assessing the impact of these molecules on mitochondrial fusion and functionality.
  • Analyzing cellular responses, including outer membrane permeabilization, caspase activation, DNA damage, and gene expression.

Main Results:

  • Small molecules were identified that either increase or inhibit mitofusin activity.
  • Mitofusin activation promoted mitochondrial fusion and functionality.
  • Mitofusin inhibition decreased mitochondrial fusion and functionality, induced mitochondrial outer membrane permeabilization, sub-lethal caspase-3/7 activation, DNA damage, and upregulated DNA damage response genes.
  • Mitofusin inhibition potentiated apoptosis induced by SMAC mimetics.

Conclusions:

  • Small molecules can pharmacologically target mitofusins.
  • Mitofusin activity is a critical determinant of mitochondrial fusion and cellular health.
  • Mitofusin inhibition has complex downstream effects, including DNA damage induction and potentiation of apoptosis.

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