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Do free radicals flip a ATP synthase switch?
- Richard G Fiddian-Green (10 October 2005)
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Is increasing FiO2 above 0.2 always harmful?
- Richard G Fiddian-Green (23 March 2005)
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Richard G Fiddian-Green, FRCS,FACS None
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ATP synthase acts like a rotary pump seemingly allowing protons to enter the mitochondrium [with ADP and Pi] for ATP resynthesis and pumping protons out of the mitochondrion to reestablish the proton gradient when ATP synthase is reversed. If so what induces the ATP synthase reversal? Free radicals? If so the effect would be anlaogous to uncoupling but without membrane damage. It might even be an evolutionary preserved mechanism for preventing oxygen toxicity. Conflict of Interest:None declared |
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Richard G Fiddian-Green, FRCS, FACS None
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This is an important observation for it raises the possibility that a high FiO2 might increase both fetal and maternal risks. Free radicals are generated in the electron transport chain especially when xanthine dehydrogenase has been converted into xanthine oxidase. The inference is that the generation of free radicals depends not only upon the availability of oxygen but also upon the rate of oxidative phosphorylation. When free radicals are generated in gut enterocytes, for example, a shift in dependence of ATP resynthesis occurs from oxidative phosphorylation (1) to anaerobic glycolysis (2) and oxidative phosphorylation is uncoupled increasing thermogenesis and with it temperature, metabolic rate, oyxgen consumption and net ATP yield [Q10 effect]. This depends upon the supply of adequate substrate and the capacity to washout and recycle anaerobic metabolites in adequately oxygenated organs notably the liver. The factors that induce the release of injurous levels of free radicals might, therefore, include an increase in availability of oxygen [as this study showed (3)], an increase in [AMP] induced by a decline in energy charge, and an increase in concentration of xanthine oxidase. The decline in energy charge could be induced by cellular stresses that deplete ATP (and consequently elevate AMP), either by inhibiting ATP production (e.g., ischaemia), or by accelerating ATP consumption (e.g., physical exertion during labour) (4). Cytokine release can be an especially important cause of a decline in energy charge for it stimulates the conversion of xanthine dehydrogenase into xanthine oxidase, accelerates ATP cumsumption, need for ATP resynthesis, likelhood of generating the AMP needed for free radical generation, and depletes adenine nucleotide pools by accelerating the irreversible degradation of AMP into uric acid. The most important causes of cytokine release during a Caesarian can be expected to be shock, the transfusion of blood products, surgical trauma (5), and possibly by the anaerobic glycolysis induced by a sudden increase in tissue pH in exposed tissues (6). One wonders just what it is that precipitates the monumental changes in fetal physiology that occur so aburptly with parturition. My guess is that like most growing tissues the fetus depends primarily upon anaerobic glycolysis for its ATP needs until parturition when it no longer has the luxury of placental support to sustain the high flow rates needed to avoid a decline in energy charge sufficient to cause congenital anomalies especially in the developing heart which would be the most vulnerable. [What happens in eggs?] The need for nutrient delivery should accelerate with placental separation and induce a decline in Daniel Atkinson energy charge that activates the AMP-activated protein kinase cascade switching on catabolic pathways, both acutely by phosphorylation of metabolic enzymes and chronically by effects on gene expression, and switches off many ATP- consuming processes. These are likely to be accompanied by a fall in systemic and intracerebral pH to levels that are able to trigger the respiratory efforts rewarded by the baby's cry but not able to generate xanthine oxidase [A quick Pubmed check suggsts that the xanthine oxidase may also be able to generate free radicals in the fetus(7)]. Limiting myocardial workload at this stage, possibly best achieved by some degree of tissue acidosis to upregulate oxidative phosphorylation, must be in the baby's best interests. Giving oxygen could compromise that by generating free radicals that inhibit oxygen consumption and increase dependence upon anaerobic glycolysis. The heart is not the only organ at risk of oxygen toxicity as is common knowledge in neonatal ICUs. A legitmate question is does increasing FiO2 ever do more good than harm even in hypoxaemia? The most effective treatment of hypoxaemia, judged from the reversal of the cyanosis, is addressing any airway obstruction. The benefit may, however, be derived from reducing the tissue pCO2 for when elevated it inhibits oxidative phosphorylation by mass action. Reversing the cyanosis might be incidental. The only time supplemental oxygen is of any benefit might be in hypobaric hypoxia and in a fall in FiO2 below 0.2 such as that which effectively occurs in carbon monoxide poisoning. That so many healthy babies are born despite supplementary oxygen suggests that real harm may only be done if xanthine dehydrogenase has been converted into xanthine oxidase. The problem is that these are the infants in whom it is most likely to be a straw that breaks the camel's back. 1.Khan AU, Delude RL, Han YY, Sappington PL, Han X, Carcillo JA, Fink MP. Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L1082-91. 2. Berg S, Sappington PL, Guzik LJ, Delude RL, Fink MP. Proinflammatory cytokines increase the rate of glycolysis and adenosine-5' -triphosphate turnover in cultured rat enterocytes. Crit Care Med. 2003 Apr;31(4):1203-12. 3. K. S. Khaw, C. C. Wang, W. D. Ngan Kee, C. P. Pang, and M. S. Rogers Effects of high inspired oxygen fraction during elective Caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation Br. J. Anaesth. 2002; 88: 18-23 4. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001 Dec;23(12):1112-9. 5. Fiddian-Green RG. Open versus laparoscopy assisted colectomy. Lancet. 2003 Jan 4;361(9351):74; author reply 75-6. 6. Product of a tissue alkalosis induced by hypocarbia? Richard G Fiddian-Green (6 March 2005) eLetter re: T Tsubo, T Kudo, A Matsuki, and T Oyama Decreased glucose utilization during prolonged anaesthesia and surgery Can J Anesth 1990; 37: 645-649 7. Iwata H, Akamatsu S, Minami N, Yamada M.7 Allopurinol, an inhibitor of xanthine oxidase, improves the development of IVM/IVF bovine embryos (>4 cell) in vitro under certain culture conditions. Theriogenology. 1999 Feb;51(3):613-22. Conflict of Interest:Patents issued in my name |
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