Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate
| Autor: | Ramya Ranganathan, Joseph M. Bateman, Navdeep S. Chandel, Gregory S. McElroy, Lucy Granat, Rachel J. Hunt |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cell physiology
Male Biology Mitochondrion Endoplasmic Reticulum Glutarates 03 medical and health sciences 0302 clinical medicine Report Animals Drosophila Proteins Transcription factor Research Articles 030304 developmental biology Cell Nucleus Neurons 0303 health sciences Mucous Membrane Endoplasmic reticulum ATF4 Brain Cell Biology Endoplasmic Reticulum Stress Activating Transcription Factor 4 Cell biology Mitochondria Drosophila melanogaster nervous system Unfolded protein response Unfolded Protein Response Female Signal transduction 030217 neurology & neurosurgery Function (biology) Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Hunt et al. show that mitochondrial stress in Drosophila neurons activates ATF4 expression, resulting in increased L-2-hydroxyglutarate (L-2-HG) levels. Reducing L-2-HG levels improves neuronal activity, demonstrating that increased L-2-HG contributes to neuronal dysfunction. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|