The role of ATF4 in neurons under mitochondrial stress
Abstract
Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.
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BibTeX
@article{bilen2026role,
title = {{The role of ATF4 in neurons under mitochondrial stress}},
author = {Maria Bilen and Yubing Liu and Imane Chakroun and Mohamed Ariff Iqbal and Bensun Fong and Jingwei Chen and Smitha Paul and Alexandre Blais and Ruth Slack},
journal = {NAR Genomics and Bioinformatics},
year = {2026},
month = sep,
doi = {10.1093/nargab/lqag069},
url = {https://hal.science/hal-05794832v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - The role of ATF4 in neurons under mitochondrial stress
AU - Maria Bilen
AU - Yubing Liu
AU - Imane Chakroun
AU - Mohamed Ariff Iqbal
AU - Bensun Fong
AU - Jingwei Chen
AU - Smitha Paul
AU - Alexandre Blais
AU - Ruth Slack
PY - 2026
DA - 2026/09/27
JO - NAR Genomics and Bioinformatics
DO - 10.1093/nargab/lqag069
UR - https://hal.science/hal-05794832v1
AB - Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.
SN - 2631-9268
ER -