Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Abstract

The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression.

Proteomic and metabolomic signatures associated with the immune response in healthy individuals immunized with an inactivated SARS-CoV-2 vaccine

“…In our data, the essential intermediary metabolites in the TCA cycle were changed in vaccine immunized samples. These TCA cycle intermediary metabolites play a crucial role in regulating the immune system with some activating the immune response and others suppressing it (Choi et al, 2021). In cells with infection or other stresses, TCA cycle intermediates may accumulate and regulate inflammatory gene expression (Tannahill et al, 2013; Williams and O’Neill, 2018).…”

The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections

“…Comprehensive reviews on metabolic pathways, including the TCA cycle and their role beyond metabolism, have recently been published ( Claus and Liebert, 2014 ; O´Neill et al, 2016 ; Williams and O´Neill, 2018 ; Martínez-Reyes and Chandel, 2020 ; Choi et al, 2021 ). In brief, the TCA cycle (also known as Krebs cycle or citric acid cycle) takes place within mitochondria and initiates with a reaction catalyzed by the enzyme citrate synthase, leading to the synthesis of citrate from the condensation of oxaloacetate with acetyl-coenzyme-A.…”

Signals from the Circle: Tricarboxylic Acid Cycle Intermediates as Myometabokines

“…Further signaling properties of citrate are known from studies on its role in immune regulation and tumorigenesis [ 16 , 18 , 55 ]: cytosolic citrate is cleaved into acetyl-CoA and oxaloacetate through the enzyme ATP-citrate lyase, and can provide the acetyl moiety for histone acetylation, which has been implicated in the activation of glycolytic and proliferative genes [ 56 ]. Furthermore, citrate-derived metabolites such as itaconate, oxaloacetate, acetyl-CoA, and fatty acids have been implicated in the regulation of inflammatory cytokine activation and NO and ROS production.…”

“…Among the metabolites fulfilling these criteria, intermediates of the tricarboxylic acid (TCA) cycle are particularly intriguing myometabokine candidates. Current immunologic and cancer research provided new insights into the signaling properties of TCA cycle metabolites, which often accumulate during the metabolic reprogramming of tumor cells and were, therefore, named oncometabolites [ 16 , 17 , 18 ]. The growing knowledge of the physiological importance of receptors and transporters of TCA cycle metabolites, and their connection to intracellular signaling pathways and epigenetic modifications, contributes to a picture of TCA metabolites as second messengers, and of the TCA cycle as a signaling hub [ 19 , 20 , 21 ].…”