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

Rachel J. Hunt, Lucy Granat, Gregory S. McElroy, Ramya Ranganathan, Navdeep S. Chandel, Joseph M. Bateman

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4007-4016
Number of pages10
JournalJournal of Cell Biology
Volume218
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Cell Biology

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