Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts

Nat Commun. 2019 Aug 13;10(1):3645. doi: 10.1038/s41467-019-11636-5.


Chronic mitochondrial stress associates with major neurodegenerative diseases. Recovering stressed mitochondria constitutes a critical step of mitochondrial quality control and thus energy maintenance in early stages of neurodegeneration. Here, we reveal Mul1-Mfn2 pathway that maintains neuronal mitochondrial integrity under stress conditions. Mul1 deficiency increases Mfn2 activity that triggers the first phasic mitochondrial hyperfusion and also acts as an ER-Mito tethering antagonist. Reduced ER-Mito coupling leads to increased cytoplasmic Ca2+ load that activates calcineurin and induces the second phasic Drp1-dependent mitochondrial fragmentation and mitophagy. Overexpressing Mfn2, but not Mfn1, mimics Mul1-deficient phenotypes, while expressing PTPIP51, an ER-Mito anchoring protein, suppresses Parkin-mediated mitophagy. Thus, by regulating mitochondrial morphology and ER-Mito contacts, Mul1-Mfn2 pathway plays an early checkpoint role in maintaining mitochondrial integrity. Our study provides new mechanistic insights into neuronal mitochondrial maintenance under stress conditions, which is relevant to several major neurodegenerative diseases associated with mitochondrial dysfunction and altered ER-Mito interplay.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitophagy*
  • Neurons / cytology
  • Neurons / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Mitochondrial Proteins
  • MUL1 protein, mouse
  • Ubiquitin-Protein Ligases
  • parkin protein
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse
  • Calcium