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. The increased

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

ic ratio of free NADH/NAD⁺ in cells (more NADH than NAD⁺) can be caused by diabetic

hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...

and by excessive alcohol consumption. Low levels of TPP results from

thiamine deficiency Thiamine deficiency is a medical condition of low levels of thiamine (vitamin B1). A severe and chronic form is known as beriberi. The name beriberi was possibly borrowed in the 18th century from the Sinhala language, Sinhalese phrase (bæri ...

. The insufficiency of available NAD⁺ or TPP produces symptoms similar to hypoxia (lack of oxygen), because they are needed primarily by the

Krebs cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...

for

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

, and NAD⁺ to a lesser extent in anaerobic glycolysis. 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 Anaerobic glycolysis is the transformation of glucose to lactate when limited amounts of oxygen (O2) are available. This occurs in health as in exercising and in disease as in sepsis and hemorrhagic shock. providing energy for a period ranging fr ...

is excessively used which turns glycogen and glucose into pyruvate, and then the pyruvate into lactate (

fermentation Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...

). 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 Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and lo ...

. The decreased pyruvate inhibits

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

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 Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes i ...

). 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 Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper r ...

). Pseudohypoxia also leads to

hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 ...

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 The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP conv ...

. 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. It is expected that human NAD trials will begin in 2014. Pseudohypoxia is a feature commonly noted in poorly-controlled

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

Reactions

In 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. 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⁺. In ethanol catabolism, ethanol is converted into acetate, consuming NAD⁺. 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.

Diabetes

Polyol pathway

D-glucose + NADPH → Sorbitol + NADP⁺ (catalyzed by aldose reductase) Sorbitol + NAD⁺ → D-fructose + NADH (catalyzed by sorbitol dehydrogenase)

Poly (ADP-ribose) polymerase-1

Protein + NAD⁺ → Protein + ADP-ribose + nicotinamide (catalyzed by PARP1)

Ethanol catabolism

Alcohol dehydrogenase

Ethanol + NAD⁺ → Acetaldehyde + NADH + H⁺ (catalyzed by alcohol dehydrogenase) Acetaldehyde + NAD⁺ → Acetate + NADH + H⁺ (catalyzed by aldehyde dehydrogenase)

MEOS

Ethanol + NADPH + H⁺ + O₂ → Acetaldehyde + NADP⁺ + 2H₂O (catalyzed by CYP2E1) Acetaldehyde + NAD⁺ → Acetate + NADH + H⁺ (catalyzed by aldehyde dehydrogenase)

References

{{reflist Cell biology Medical signs Geriatrics Senescence