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Abstract
The Tricarboxylic Acid (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.
Highlights
Most of the energy-rich adenosine triphosphate (ATP) generated in metabolism is provided by the complete oxidation of key fuel molecules to CO2 in mitochondria
We targeted two Tricarboxylic Acid Cycle (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)
Summary
Most of the energy-rich adenosine triphosphate (ATP) generated in metabolism is provided by the complete oxidation of key fuel molecules to CO2 in mitochondria. This catabolic process primarily occurs in the mitochondrial matrix via a series of reactions known as the. SDH is the only TCA cycle enzyme that is a component of the ETC and so provides a physical link between the TCA cycle and oxidative phosphorylation (OXPHOS). Mutations of both FH and SDH predispose kidney tubuluar epithelium to transformation (Sciacovelli et al, 2020), indicating that the kidney can be affected by TCA cycle dysfunction
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