bims-smemid 2024-09-29 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2024–09–29
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
eIF2B localization and its regulation during the integrated stress response is cell-type specific.

Nat Commun. 2024 Sep 27. 15(1): 8301

Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.

Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.

The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.

DOI: https://doi.org/10.1038/s41467-024-52538-5
iScience. 2024 Sep 20. 27(9): 110851

eIF2B localization and its regulation during the integrated stress response is cell-type specific.

Filipe M Hanson, Madalena I Ribeiro de Oliveira, Alison K Cross, K Elizabeth Allen, Susan G Campbell.

  Eukaryotic initiation factor 2B (eIF2B) controls translation initiation by recycling inactive eIF2-GDP to active eIF2-GTP. Under cellular stress, the integrated stress response (ISR) is activated inhibiting eIF2B activity resulting in the translation attenuation and reprogramming of gene expression to overcome the stress. The ISR can dictate cell fate wherein chronic activation has pathological outcomes. Vanishing white matter disease (VWMD) is a chronic ISR-related disorder with mutations in eIF2B targeting astrocyte and oligodendrocyte cells. Regulation of eIF2B localization (eIF2B bodies) has been implicated in the ISR. We present evidence that neuronal and glial cell types possess distinct patterns of eIF2B bodies which change in a manner correlating to acute and chronic ISR activation. We also demonstrate that while neural and glial cell types respond similarly to the acute induction of the ISR a chronic ISR exerts cell-type specific differences. These findings provide key insights into neural cell responses and adaptation to cellular stress.

Keywords:  Biological sciences; Cell; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110851