The tricarboxylic acid cycle, an ancient metabolic network with a novel twist.
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 FADH(2)) 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 alpha-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 alpha-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.
Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada.
Ryan J
RJ
Mailloux
Robin
R
Bériault
Joseph
J
Lemire
Ranji
R
Singh
Daniel R
DR
Chénier
Robert D
RD
Hamel
Vasu D
VD
Appanna
D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002952:Citric Acid Cycle / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000378:metabolism; D015227:Lipid Peroxidation; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008670:Metals / Q000737:chemistry; D009243:NAD / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D011551:Pseudomonas fluorescens / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024483:Vitamin K 3 / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D007656:Ketoglutaric Acids; D008670:Metals; D016877:Oxidants; D011506:Proteins; D017382:Reactive Oxygen Species; D014815:Vitamins; D009243:NAD; D024483:Vitamin K 3; D006861:Hydrogen Peroxide