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J Cell Biol. 2019 Oct 23. pii: jcb.201904148. doi: 10.1083/jcb.201904148. [Epub ahead of print]

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

Author information

1
Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
2
Department of Medicine and Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL.
3
Department of Medicine and Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL joseph_matthew.bateman@kcl.ac.uk nav@northwestern.edu.
4
Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK joseph_matthew.bateman@kcl.ac.uk.

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.

PMID:
31645461
DOI:
10.1083/jcb.201904148

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