Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism

 

Re-written summaries by: Anuva Gajjar

Date Published: 11/12/2022

Original research links:

https://pubmed.ncbi.nlm.nih.gov/34939929/

Introduction:

The study "Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism" by Ryan et al. focuses on the understanding the relationship between the Tricarboxylic acid (TCA) cycle, a key metabolic pathway, and the stress response pathway, specifically the role of Activating Transcription Factor 4 (ATF4) in the integration of redox and amino acid metabolism. The TCA cycle is a series of chemical reactions that occur in cells, and it is essential for the production of energy through the oxidation of acetyl-CoA. The disruption of TCA cycle can lead to the accumulation of toxic intermediates and the depletion of energy-rich molecules, which can cause cellular stress. The authors aim to investigate the impact of TCA cycle disruption on the stress response pathway and to understand the mechanism by which the TCA cycle and stress response pathway are integrated.

​

Methods:

The authors used a combination of genetic, biochemical, and metabolic approaches to study the impact of TCA cycle disruption on the stress response pathway in mouse and human cells. They used genetic knock-out and knock-down approaches to disrupt the TCA cycle by targeting different components of the cycle such as succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) and study the effect on stress response pathways. They also used mass spectrometry-based metabolic profiling to identify changes in the metabolic state of cells in response to TCA cycle disruption. They also used qRT-PCR, Western blotting, and ChIP-seq to study the effect of TCA cycle disruption on the expression of stress response genes and the binding of ATF4 to target genes.

​

Results:

The authors found that TCA cycle disruption leads to an activation of the stress response pathway, specifically the ATF4-dependent stress response pathway. They found that TCA cycle disruption leads to an increase in the levels of ATF4 and its binding to target genes involved in redox and amino acid metabolism. They also found that the activation of the ATF4-dependent stress response pathway is essential for the integration of redox and amino acid metabolism in response to TCA cycle disruption. The study also showed that the activation of ATF4-dependent stress response pathway led to a switch in the metabolic pathways from TCA cycle to amino acid metabolism, which is essential for the cells to adapt to the TCA cycle disruption.

​

Conclusion:

The study concludes that TCA cycle disruption leads to an activation of the stress response pathway, specifically the ATF4-dependent stress response pathway. The authors suggest that the integration of redox and amino acid metabolism by the ATF4-dependent stress response pathway is essential for the adaptation of cells to TCA cycle disruption. This mechanism allows the cells to switch from the TCA cycle to amino acid metabolism, which provides the necessary energy and precursors to maintain cellular home the ATF4-dependent stress response pathway. The authors suggest that the integration of redox and amino acid metabolism by the ATF4-dependent stress response pathway is essential for the adaptation of cells to TCA cycle disruption. This mechanism allows the cells to switch from the TCA cycle to amino acid metabolism, which provides the necessary energy and precursors to maintain cellular homeostasis. The authors also suggest that their findings have implications for understanding the mechanisms underlying cellular stress and its impact on metabolic homeostasis. They also suggest that the understanding of the role of ATF4 in the integration of redox and amino acid metabolism could have implications for the development of therapies for metabolic disorders such as cancer, heart disease and neurological disorders. The study provides a deeper understanding of the metabolic pathways and the mechanism of cellular stress response and adaptation which is essential for the development of new therapeutic strategies.

​

​