The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling

Cell. 2018 Aug 9;174(4):870-883.e17. doi: 10.1016/j.cell.2018.06.029. Epub 2018 Jul 26.


The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPRmt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPRmt. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPRmt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.

Keywords: EGL-20; UPR(mt); VPS-35; Wnt signaling; mitochondrial unfolded protein response; mitokine; retromer complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Animals, Genetically Modified / growth & development
  • Animals, Genetically Modified / metabolism*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Polyubiquitin / metabolism*
  • Unfolded Protein Response / physiology*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*


  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • Egl-20 protein, C elegans
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Mig-14 protein, C elegans
  • VPS-35 protein, C elegans
  • Vesicular Transport Proteins
  • Wnt Proteins
  • Polyubiquitin