Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response

Cell. 2016 Sep 8;166(6):1539-1552.e16. doi: 10.1016/j.cell.2016.08.027.


Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimer's, Parkinson's, and Huntington's. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small-molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cell Line
  • Cytosol / physiology*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Heat-Shock Proteins / genetics
  • Heat-Shock Response / physiology*
  • Homeostasis
  • Humans
  • Lipid Metabolism / genetics
  • Lipids / biosynthesis*
  • Mitochondria / physiology*
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / genetics
  • Protein Folding
  • Unfolded Protein Response / physiology*


  • Heat-Shock Proteins
  • Lipids
  • Mitochondrial Proteins
  • Molecular Chaperones