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

Abstract

The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response

“…We focused on the intersecting genes that were upregulated after ONC (ONC/Ctrl; fold change > 1.5; p < 0.05) and recovered in TPEN (TPEN/ONC; fold change < −1.5; p < 0.05), namely, TPEN target genes ( Figure 7 B). Using a signature of mitochondrial ISR-related genes curated from the literature [ 28 , 52 , 53 , 54 , 55 ], we confirmed the significant enrichment of ISR-induced inflammatory mediators (e.g., Il1b and Tnf), eif2α-phosphorylation factors (e.g., Eif2ak2), and ATF4 targets (e.g., Slc7a11, Asns, and Cebpb) with intersecting genes ( Figure 7 C). Of note, the phosphorylation of eIF2α is mediated by four eIF2α kinases (HRI, PKR, PERK, and GCN2) encoded by Eif2ak1-4.…”

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

“…Mitochondria are essential components for many metabolic pathways, namely the TCA cycle and the electron chain. They are crucial for maintaining many aspects of cellular homeostasis [ 48 , 49 ]. During metabolic reprogramming, mitochondria change from primarily being used for energy production, by way of the mitochondrial electron transport chain, to playing a role in generating TCA cycle metabolites to be used in the biogenesis and redox balance [ 50 ].…”

FOXA2 controls the anti-oxidant response in FH-deficient cells

“…Among the enriched motifs in more active regions were NRF2, ATF4 and MAF motifs. These motifs map to transcription factors known to be active in FH-deficient cells (Adam et al, 2011;Ooi et al, 2011;Ryan et al, 2021). Conversely, ZEB, GRHL and NFKB/RELA motifs were enriched in less active regions.…”