MFN2 retrotranslocation boosts mitophagy by uncoupling mitochondria from the ER

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Gian-Luca McLelland1, Edward A Fon1

  • 1a McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute and Department of Neurology and Neurosurgery , McGill University , Montreal , Canada.

Autophagy
|August 8, 2018
PubMed

Insights

The endoplasmic reticulum-mitochondria tether MFN2 suppresses mitophagy by linking these organelles. Parkinson disease proteins PINK1 and PRKN disrupt this tether, promoting the removal of damaged mitochondria.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Autophagy

Background:

  • Mitochondrial damage activates quality control pathways to maintain mitochondrial network health.
  • Mitophagy, the selective removal of damaged mitochondria, is crucial for cellular homeostasis.
  • Parkinson disease-linked genes, including PRKN (Parkinson's disease 2, E3 ubiquitin protein ligase) and PINK1 (PTEN-induced kinase 1), are key initiators of mitophagy.

Purpose of the Study:

  • To investigate the role of endoplasmic reticulum (ER) and outer mitochondrial membrane (OMM) contact sites in the mitophagy pathway.
  • To elucidate the function of the ER-OMM tether MFN2 (Mitofusin 2) in regulating mitophagy initiation.

Main Methods:

  • Investigated the interaction between ER and OMM using cellular models.
  • Analyzed the role of MFN2 in controlling the accessibility of mitochondrial substrates to PINK1 and PRKN.
  • Examined the effects of PINK1, PRKN, and VCP (Valosin-containing protein) on ER-OMM contact and MFN2 localization.

Main Results:

  • The ER-OMM tether MFN2 acts as a suppressor of mitophagy.
  • MFN2's ability to link the OMM to the ER may limit substrate accessibility for PINK1 and PRKN.
  • PINK1, PRKN, and VCP promote the disruption of ER-mitochondria contact by inducing MFN2 ubiquitination, retrotranslocation, and turnover from the OMM.

Conclusions:

  • MFN2 plays a critical role in regulating mitophagy by tethering the ER to the OMM.
  • The interplay between ER-mitochondria contact and mitophagy initiation is mediated by MFN2 dynamics.
  • Outer mitochondrial membrane remodeling is a key regulatory step in the mitophagy pathway.
Keywords:
Contact siteMFN2PINK1-PRKN pathwayParkinson’s diseasemitophagyphosphoubiquitin

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