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Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial

Chuang-Rung Chang1, Craig Blackstone

  • 1Cellular Neurology Unit, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.

The Journal of Biological Chemistry
|June 8, 2007
PubMed

Insights

Phosphorylation of the Drp1 protein at Serine 637 by cAMP-dependent protein kinase inhibits mitochondrial division. This key regulatory mechanism impacts mitochondrial dynamics and cellular function.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitochondria form a dynamic network through fission and fusion.
  • The dynamin-like protein 1 (Drp1) is essential for mitochondrial division.
  • Regulation of Drp1 activity is crucial for mitochondrial dynamics but not fully understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms of Drp1.
  • To identify specific phosphorylation sites on Drp1 and their functional consequences.
  • To elucidate the role of Drp1 phosphorylation in mitochondrial division.

Main Methods:

  • Site-directed mutagenesis to create phosphomimetic Drp1 mutants (S637D).
  • In vitro GTPase activity assays.
  • Cellular assays to assess mitochondrial morphology and fission.
  • Analysis of protein-protein interactions.

Main Results:

  • Identified cAMP-dependent protein kinase-dependent phosphorylation of Drp1 at Ser(637) within the GTPase effector domain (GED).
  • Phosphorylation at Ser(637) inhibits Drp1 GTPase activity.
  • The S637D mutation impairs intramolecular interactions between GTP-binding/middle domains and the GED domain.
  • Mitochondrial fission is significantly inhibited in cells expressing the S637D phosphomimetic mutant.

Conclusions:

  • Protein phosphorylation at Ser(637) is a key regulator of Drp1 function.
  • Phosphorylation inhibits Drp1 GTPase activity by altering intramolecular domain interactions.
  • This regulatory mechanism plays a role in controlling mitochondrial division and morphology.

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