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Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis

Aswin Pyakurel1, Claudia Savoia1, Daniel Hess2

  • 1Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.

Molecular Cell
|March 25, 2015
PubMed

Insights

Extracellular-signal-regulated kinase (ERK) phosphorylates mitofusin 1 (MFN1), controlling mitochondrial shape and apoptosis. This discovery reveals a key mechanism in cellular signaling and neuronal cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Mitochondrial morphology is crucial for cellular signaling.
  • Molecular mechanisms governing mitochondrial shape remain largely unidentified.
  • Mitofusin 1 (MFN1) is a key protein in mitochondrial fusion.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating mitochondrial shape and apoptosis.
  • To identify novel targets of the mitogen-activated protein (MAP) kinase cascade.
  • To investigate the role of extracellular-signal-regulated kinase (ERK) in MFN1 function.

Main Methods:

  • Phosphoproteomic and biochemical analyses were employed.
  • Site-directed mutagenesis was used to create MFN1 phosphorylation mutants.
  • Cellular assays assessed mitochondrial morphology, fusion, and apoptosis.
  • Neuronal models of apoptosis were utilized.

Main Results:

  • Extracellular-signal-regulated kinase (ERK) phosphorylates mitofusin 1 (MFN1) at a novel site in the heptad repeat 1 domain.
  • This phosphorylation event modulates MFN1's role in mitochondrial elongation and apoptosis.
  • Constitutively phosphorylated MFN1 mutants showed impaired oligomerization and tethering but enhanced binding to BAK.
  • Neuronal apoptosis induced by oxygen-glucose deprivation and MEK/ERK activation was dependent on MFN1(T562).

Conclusions:

  • Mitofusin 1 (MFN1) is a direct target of the ERK kinase.
  • ERK-mediated phosphorylation of MFN1 regulates mitochondrial dynamics and apoptosis.
  • This pathway is critical for neuronal survival under stress conditions.

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