Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate

J Cell Biol. 2019 Dec 2;218(12):4007-4016. doi: 10.1083/jcb.201904148. Epub 2019 Oct 23.


Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Brain / metabolism*
  • Cell Nucleus / metabolism
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Female
  • Glutarates / metabolism*
  • Male
  • Mitochondria / metabolism*
  • Mucous Membrane / metabolism
  • Neurons / pathology*
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Unfolded Protein Response


  • Drosophila Proteins
  • Glutarates
  • Transcription Factors
  • crc protein, Drosophila
  • Activating Transcription Factor 4