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

TLDR

The tricarboxylic acid cycle is a core metabolic network that supplies anabolic precursors and reducing equivalents (NADH, FADH₂) for cellular energy production. The authors aim to demonstrate that the TCA cycle also functions in oxidative defense, with α‑ketoglutarate acting as a key ROS detoxifier. They show that α‑ketoglutarate can act as an antioxidant, reducing ROS and NADH formation, thereby limiting ROS release from oxidative phosphorylation. The study finds that increased α‑ketoglutarate synthesis via NADP‑ICDH and its reduced TCA utilization, together with diminished activity of KGDH, NAD‑ICDH, and SDH under oxidative stress, link the TCA cycle to ROS homeostasis and may underlie its dysfunction in disease and ageing.

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.