Pseudohypoxia refers to a condition that mimics hypoxia, by having sufficient oxygen yet impaired mitochondrial respiration due to a deficiency of necessary co-enzymes, such as NAD and TPP.[1][2][3] The increased cytosolic ratio of free NADH/NAD in cells (more NADH than NAD ) can be caused by diabetic hyperglycemia and by excessive alcohol consumption.[2][3] Low levels of TPP results from thiamine deficiency.[1][4]
The insufficiency of available NAD or TPP produces symptoms similar to hypoxia (lack of oxygen), because they are needed primarily by the Krebs cycle for oxidative phosphorylation, and NAD to a lesser extent in anaerobic glycolysis.[3] Oxidative phosphorylation and glyocolysis are vital as these metabolic pathways produce ATP, which is the molecule that releases energy necessary for cells to function.
As there is not enough NAD or TPP for aerobic glycolysis nor fatty acid oxidation, anaerobic glycolysis is excessively used which turns glycogen and glucose into pyruvate, and then the pyruvate into lactate (fermentation). Fermentation also generates a small amount of NAD from NADH, but only enough to keep anaerobic glycolysis going. The excessive use of anaerobic glycolysis disrupts the lactate/pyruvate ratio causing lactic acidosis. The decreased pyruvate inhibits gluconeogenesis and increases release of fatty acids from adipose tissue. In the liver, the increase of plasma free fatty acids results in increased ketone production (which in excess causes ketoacidosis). The increased plasma free fatty acids, increased acetyl-CoA (accumulating from reduced Krebs cycle function), and increased NADH all contribute to increased fatty acid synthesis within the liver (which in excess causes fatty liver disease).[3]
Pseudohypoxia also leads to hyperuricemia as elevated lactic acid inhibits uric acid secretion by the kidney; as well as the energy shortage from inhibited oxidative phosphorylation leads to increased turnover of adenosine nucleotides by the myokinase reaction and purine nucleotide cycle.[3]
Research has shown that declining levels of NAD during aging cause pseudohypoxia, and that raising nuclear NAD in old mice reverses pseudohypoxia and metabolic dysfunction, thus reversing the aging process.[5] It is expected that human NAD trials will begin in 2014.[6]
Pseudohypoxia is a feature commonly noted in poorly-controlled diabetes.[2]
Reactions
editIn poorly controlled diabetes, as insulin is insufficient, glucose cannot enter the cell and remains high in the blood (hyperglycemia). The polyol pathway converts glucose into fructose, which can then enter the cell without requiring insulin.[7][8] The oxidative damage done to cells in diabetes damages DNA and causes poly (ADP ribose) polymerases or PARPs to be activated, such as PARP1. Both processes reduce the available NAD .[7]
In ethanol catabolism, ethanol is converted into acetate, consuming NAD .[3] When alcohol is consumed in small quantities, the NADH/NAD ratio remains in balance enough for the acetyl-CoA (converted from acetate) to be used for oxidative phosphorylation. However, even moderate amounts of alcohol (1-2 drinks) results in more NADH than NAD , which inhibits oxidative phosphorylation. In chronic excessive alcohol consumption, the microsomal ethanol oxidizing system (MEOS) is used in addition to alcohol dehydrogenase.[3]
Diabetes
editPolyol pathway
editD-glucose NADPH → Sorbitol NADP (catalyzed by aldose reductase)
Sorbitol NAD → D-fructose NADH (catalyzed by sorbitol dehydrogenase)
Poly (ADP-ribose) polymerase-1
editProtein NAD → Protein ADP-ribose nicotinamide (catalyzed by PARP1)
Ethanol catabolism
editAlcohol dehydrogenase
editEthanol NAD → Acetaldehyde NADH H (catalyzed by alcohol dehydrogenase)
Acetaldehyde NAD → Acetate NADH H (catalyzed by aldehyde dehydrogenase)
MEOS
editEthanol NADPH H O2 → Acetaldehyde NADP 2H2O (catalyzed by CYP2E1)
Acetaldehyde NAD → Acetate NADH H (catalyzed by aldehyde dehydrogenase)
See also
edit- Hypoxia (medical)
- Hypoxia (disambiguation) - list under Hypoxia (medical) e.g. Intrauterine hypoxia
- Bioenergetic systems - metabolic pathways of producing ATP
- Metabolic acidosis
References
edit- ^ a b C, Marrs; D, Lonsdale (2021-09-29). "Hiding in Plain Sight: Modern Thiamine Deficiency". Cells. 10 (10): 2595. doi:10.3390/cells10102595. ISSN 2073-4409. PMC 8533683. PMID 34685573.
- ^ a b c Williamson, Joseph R.; Chang, Katherine; Frangos, Myrto; Hasan, Khalid S.; Ido, Yasuo; Kawamura, Takahiko; Nyengaard, Jens R.; Den Enden, Maria van; Kilo, Charles; Tilton, Ronald G. (1993). "Hyperglycemic Pseudohypoxia and Diabetic Complications". Diabetes. 42 (6): 801–813. doi:10.2337/diab.42.6.801. PMID 8495803. S2CID 21503889.
- ^ a b c d e f g Coffee, Carole J. (1999). Quick Look Medicine: Metabolism. Hayes Barton Press. pp. 176–177. ISBN 1-59377-192-4.
- ^ Rl, Sweet; Ja, Zastre (2013). "HIF1-α-mediated gene expression induced by vitamin B1 deficiency". International Journal for Vitamin and Nutrition Research. 83 (3): 188–197. doi:10.1024/0300-9831/a000159. ISSN 0300-9831. PMID 24846908.
- ^ Gomes, Ana P.; Price, Nathan L.; Ling, Alvin J.Y.; Moslehi, Javid J.; Montgomery, Magdalene K.; Rajman, Luis; White, James P.; Teodoro, João S.; Wrann, Christiane D.; Hubbard, Basil P.; Mercken, Evi M.; Palmeira, Carlos M.; De Cabo, Rafael; Rolo, Anabela P.; Turner, Nigel; Bell, Eric L.; Sinclair, David A. (2013). "Declining NAD Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging". Cell. 155 (7): 1624–1638. doi:10.1016/j.cell.2013.11.037. PMC 4076149. PMID 24360282.
- ^ Milman, Oliver (20 December 2013). "Anti-ageing compound set for human trials after turning clock back for mice". The Guardian.
- ^ a b Song, Jing; Yang, Xiaojuan; Yan, Liang-Jun (2019). "Role of pseudohypoxia in the pathogenesis of type 2 diabetes". Hypoxia. 7: 33–40. doi:10.2147/HP.S202775. ISSN 2324-1128. PMC 6560198. PMID 31240235.
- ^ Bantle, John P. (June 2009). "Dietary fructose and metabolic syndrome and diabetes". The Journal of Nutrition. 139 (6): 1263S–1268S. doi:10.3945/jn.108.098020. ISSN 1541-6100. PMC 2714385. PMID 19403723.