@article{98a0ff14dabb4d73ab0f7295c4fe5c97,
title = "Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate",
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.",
author = "Hunt, {Rachel J.} and Lucy Granat and McElroy, {Gregory S.} and Ramya Ranganathan and Chandel, {Navdeep S.} and Bateman, {Joseph M.}",
note = "Funding Information: This work was funded by Alzheimer{\textquoteright}s Research UK (ARUK-IRG2017A-2) to J.M. Bateman; L. Granat is supported by the UK Medical Research Council (MR/N013700/1) and King{\textquoteright}s College London Medical Research Council Doctoral Training Partnership in Biomedical Sciences; R.J. Hunt was funded by a PhD studentship from the Guy{\textquoteright}s and St Thomas{\textquoteright} Charity. N.S. Chandel and G.S. McElroy were supported by National Institutes of Health grants AG049665-04 and T32CA9560-32, respectively. According to the UK research councils{\textquoteright} Common Principles on Data Policy, all data supporting this study will be openly available at https://doi.org/10.1083/jcb.201904148. The authors declare no competing financial interests. Funding Information: This work was funded by Alzheimer?s Research UK (ARUK-IRG2017A-2) to J.M. Bateman; L. Granat is supported by the UK Medical Research Council (MR/N013700/1) and King?s College London Medical Research Council Doctoral Training Partnership in Biomedical Sciences; R.J. Hunt was funded by a PhD studentship from the Guy?s and St Thomas? Charity. N.S. Chandel and G.S. McElroy were supported by National Institutes of Health grants AG049665-04 and T32CA9560-32, respectively. According to the UK research councils? Common Principles on Data Policy, all data supporting this study will be openly available at https://doi.org/10.1083/jcb.201904148. Publisher Copyright: {\textcopyright} 2019 Hunt et al.",
year = "2019",
month = dec,
day = "1",
doi = "10.1083/jcb.201904148",
language = "English (US)",
volume = "218",
pages = "4007--4016",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "12",
}