The Tricarboxylic Acid Cycle, an Ancient Metabolic Network with a Novel Twist

Abstract

The tricarboxylic acid (TCA) cycle is an essential metabolic network in all oxidative organisms and provides precursors for anabolic processes and reducing factors (NADH and FADH2) that drive the generation of energy. Here, we show that this metabolic network is also an integral part of the oxidative defence machinery in living organisms and α-ketoglutarate (KG) is a key participant in the detoxification of reactive oxygen species (ROS). Its utilization as an anti-oxidant can effectively diminish ROS and curtail the formation of NADH, a situation that further impedes the release of ROS via oxidative phosphorylation. Thus, the increased production of KG mediated by NADP-dependent isocitrate dehydrogenase (NADP-ICDH) and its decreased utilization via the TCA cycle confer a unique strategy to modulate the cellular redox environment. Activities of α-ketoglutarate dehydrogenase (KGDH), NAD-dependent isocitrate dehydrogenase (NAD-ICDH), and succinate dehydrogenase (SDH) were sharply diminished in the cellular systems exposed to conditions conducive to oxidative stress. These findings uncover an intricate link between TCA cycle and ROS homeostasis and may help explain the ineffective TCA cycle that characterizes various pathological conditions and ageing.

The protective effects of α-ketoacids against oxidative stress on rat spermatozoa in vitro

“…a-Ketoacids quench H 2 O 2 mainly through the reaction of nonenzymatic oxidative decarboxylation [19]. In this reaction, a-ketoglutarate is converted to succinate, which would support the tricarboxylic acid cycle [38]. Thus, a-ketoglutarate can shunt the tricarboxylic acid cycle on inactivation of ketoglutarate dehydrogenase under oxidative stress.…”

Plant respiration under low oxygen

“…It is located in the mitochondrial matrix where, by the oxidation of organic C substrates (pyruvate and/or malate), it releases CO 2 and provides reducing factors such as NAD(P)H and FADH 2 , which are primary substrates for the synthesis of ATP in the electron transport chain in mitochondria (Fernie et al, 2004;Mailloux et al, 2007;Sweetlove et al, 2010) (Figure 2). In turn, the TCA cycle provides C skeleton components and precursors for the biosynthesis of secondary metabolites such as terpenes, amino acids, and fatty acids, among others (Plaxton and Podestá, 2006;Sweetlove et al, 2010).…”

“…At the end of the cycle, OAA is regenerated for re-condensation with acetyl CoA, restarting the cycle (Figure 2) (Mailloux et al, 2007;Sweetlove et al, 2010).…”

“…The O 2 is a molecule that participates as a final electron acceptor in the transport chain complexes ; therefore, when oxygen availability decreases dramatically in the rhizosphere (anoxia, Table 1), OXPHOS is inactivated (Moller, 2001) and terminal oxidase (COX) is inhibited (Liao and Lin, 2001;Greenway and Gibbs, 2003;Mancuso and Marras, 2006;Mailloux et al, 2007). Under these conditions, plants have developed alternative pathways to aerobic respiration in order to maintain glycolysis through the regeneration of NAD + and thus obtain the energy needed to maintain key processes of metabolism such as membrane integrity and thus ion selectivity (Tadege et al, 1999), protein synthesis and turnover and regulation of cytosolic pH, among others (Blokhina et al, 2003).…”

The bio-nano-interface in predicting nanoparticle fate and behaviour in living organisms: towards grouping and categorising nanomaterials and ensuring nanosafety by design

“…Reactive oxygen species (ROS) are formed in the mitochondria during respiration. It has been shown that a healthy metabolic network plays a key role in the defense against oxidative stress through the production of enzymes and electron acceptors which participate in the detoxification of ROS [109]. Interference in the mitochondrial cycle results in oxidative stress owing to an increase in ROS, which act as second messengers to induce a cell reaction that may eventually lead to cell death.…”