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PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from

Chih-Wei Chen1, Ying-Jung Chen1, Xiaojing Cuili1

  • 1Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Autophagy
|February 5, 2026
PubMed

Insights

NME3 deficiency disrupts mitophagy by impairing Parkin (PRKN) recruitment to damaged mitochondria. This occurs because NME3 generates a lipid signal that untethers mitochondria from the endoplasmic reticulum, allowing PINK1 access to activate PRKN.

Area of Science:

  • Mitochondrial Biology
  • Neurodegenerative Disease Research
  • Cellular Signaling

Background:

  • Mitophagy, the selective degradation of damaged mitochondria, is crucial for cellular health and is PINK1/Parkin (PRKN)-dependent.
  • Deficiency in NME3, a mitochondrial outer membrane protein, is linked to fatal neurodegenerative disorders.
  • The precise role of NME3 in mitophagy and its connection to neurodegeneration remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which NME3 deficiency impairs mitophagy.
  • To investigate the role of NME3 in regulating Parkin (PRKN) recruitment to depolarized mitochondria.
  • To determine how NME3 influences mitochondria-endoplasmic reticulum (Mito-ER) interactions in the context of mitophagy.

Main Methods:

  • Utilized cell models with NME3 deficiency (knockout/knockdown) to study mitophagy.
  • Employed biochemical assays and immunofluorescence to assess Parkin (PRKN) binding and ubiquitin phosphorylation.
  • Investigated lipid signaling, specifically phosphatidic acid (PA) generation, and mitochondria-endoplasmic reticulum (Mito-ER) contact sites.

Main Results:

  • NME3 deficiency impairs Parkin (PRKN) binding to depolarized mitochondria independently of PINK1-mediated ubiquitin phosphorylation.
  • NME3 interacts with PLD6 to generate phosphatidic acid (PA) on damaged mitochondria, facilitating MFN2 proximity to PINK1.
  • Loss of NME3 leads to increased mitochondria-endoplasmic reticulum (Mito-ER) tethering, hindering Parkin (PRKN) activation.

Conclusions:

  • NME3 is essential for generating a lipid signal (PA) that promotes mitochondria-endoplasmic reticulum (Mito-ER) untethering.
  • This NME3-dependent process allows MFN2 to access PINK1, enabling feedforward activation of Parkin (PRKN) for mitophagy.
  • Dysregulation of NME3-mediated mitophagy and Mito-ER dynamics may contribute to neurodegenerative pathologies.
Keywords:
MFN2NME3PINK1PRKNmitophagyphosphatidic acid

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