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 fate of all aerobic organisms is dependent on the varying intracellular concentrations of NADH and NADPH. The former is the primary ingredient that fuels ATP production via oxidative phosphorylation, while the latter helps maintain the reductive environment necessary for this process and other cellular activities. In this study we demonstrate a metabolic network promoting NADPH production and limiting NADH synthesis as a consequence of an oxidative insult. The activity and expression of glucose-6-phosphate dehydrogenase, malic enzyme, and NADP ؉ -isocitrate dehydrogenase, the main generators of NADPH, were markedly increased during oxidative challenge. On the other hand, numerous tricarboxylic acid cycle enzymes that supply the bulk of intracellular NADH were significantly downregulated. These metabolic pathways were further modulated by NAD ؉ kinase (NADK) and NADP ؉ phosphatase (NADPase), enzymes known to regulate the levels of NAD ؉ and NADP ؉ . While in menadione-challenged cells, the former enzyme was upregulated, the phosphatase activity was markedly increased in control cells. Thus, NADK and NADPase play a pivotal role in controlling the cross talk between metabolic networks that produce NADH and NADPH and are integral components of the mechanism involved in fending off oxidative stress.If an aerobic organism is to survive, it is essential that an adequate supply of NADPH is available. This nicotinamide nucleotide provides a reductive environment that enables the oxidative cell to nullify the reactive oxygen species (ROS) generated as a consequence of oxidative phosphorylation, a process key to the generation of ATP (9,18,22). All organisms that utilize oxygen as the terminal e Ϫ acceptor have evolved intricate molecular strategies that allow them to combat the inherent dangers associated with living in an aerobic environment (11,26). Catalase, superoxide dismutase (SOD), and glutathione peroxidase are some of the enzymes that help decrease oxidative tension during aerobic respiration (4). However, the effectiveness of these proteins as the scavengers of ROS depends on the availability of NADPH. This nucleotide supplies the reductive power necessary to quell the oxidative potential of ROS. Hence, the production of this reducing agent is an integral part of the oxidative energy-generating machinery of all aerobic organisms. Production of ATP via oxidative phosphorylation cannot proceed effectively in the absence of a continual supply of NADPH (14, 31).Glucose-6-phosphate dehydrogenase (G6PDH), NADP ϩ -isocitrate dehydrogenase (ICDH-NADP ϩ ), malic enzyme (ME), 6-phosphogluconate dehydrogenase (6PGDH), and glutamate dehydrogenase-NADP ϩ (GDH-NADP ϩ ) are some of the important enzymes that enable aerobic cells to fulfill their requirement for NADPH (34). NADH, which is generated essentially during the catabolism of acetyl-coenzyme A via the tricarboxylic acid (TCA) cycle, is a potent prooxidant as its downstream metabolism mediated by complexes I, III, and IV produces the majority of the ROS generated in...
Lactate has long been regarded as an end product of anaerobic energy production and its fate in cerebral metabolism has not been precisely delineated. In this report, we demonstrate, for the first time, the ability of a human astrocytic cell line (CCF-STTG1) to consume lactate and to generate ATP via oxidative phosphorylation. 13C-NMR and HPLC analyses aided in the identification of tricarboxylic acid (TCA) cyle metabolites and ATP in the astrocytic mitochondria incubated with lactate. Oxamate, an inhibitor of lactate dehydrogenase (LDH), abolished mitochondrial lactate consumption. Electrophoretic and fluorescence microscopic analyses helped localize LDH in the mitochondria. Taken together, this study implicates lactate as an important contributor to ATP metabolism in the brain, a finding that may significantly change our notion of how this important organ manipulates its energy budget.
The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.
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