Accumulation of methylmalonic acid caused by vitamin B₁₂-deficiency disrupts normal cellular metabolism in rat liver

Abstract

To clarify the relationship between intracellular concentrations of methylmalonic acid and metabolic and growth inhibition in vitamin B,,deficient rats, hepatic methylmalonic acid levels were assayed and inhibition of glucose and glutamic acid metabolism by methylmalonic acid was studied in isolated hepatocytes. Vitamin B,,deficient rats (14 weeks old) excreted more urinary methylmalonic acid and had lower body weights than the control rats. Hepatic methylmalonic acid levels (3-6 (SD 1.30)-5.3 (SD 0.51) pmol/g tissue; 7.9 (SD 290)-11-8 (SD 1-14) mM) were increased and correlated with the extent of the growth retardation during vitamin B,,deficiency. Isolated hepatocytes and mitochondria from normally fed rats were labelled with ["Cc(Ullglucose and [14C(LJ)]glutamic acid respectively, in the presence or absence of Sm-methylmalonic acid. Although methylmalonic acid did not atTect the incorporation of "C into protein and organic acid fractions in the hepatocytes, it inhibited 14C02 formation (an index of glucose oxidation by the Krebs cycle) by 25 % and incorporation of I4C into the amino acid fraction by 30%. In the mitochondria, methylmalonic acid inhibited "CO, formation (indicating glutamic acid oxidation by the Krebs cycle) by 70%, but not the incorporation of I4C into the protein fraction. The incorporation of I4C into the organic acid fraction was significantly stimulated by the addition of methylmalonic acid. These results indicate that the unusual accumulation of methylmalonic acid caused by vitamin B,,deficiency disrupts normal glucose and glutamic acid metabolism in rat liver, probably by inhibiting the Krebs cycle.

Abnormal Increase in the Expression Level of Proliferating Cell Nuclear Antigen (PCNA) in the Liver and Hepatic Injury in Rats with Dietary Cobalamin Deficiency

“…In addition, methylmalonic acid is produced by the hydrolysis of methylmalonyl-CoA, accumulated in the plasma and tissues, and excreted abnormally into the urine (methylmalonic aciduria) (1,2,16). It has been reported that methylmalonic acid, when accumulated in the liver, decreases respiratory activity by inhibiting the succinate dehydrogenase reaction (2, 7).…”

“…In mammals under Cbl-deficient conditions, methionine synthase and methylmalonyl-CoA mutase activities are greatly lowered due to the defect in their coenzymes, MeCbl and AdoCbl, and hematological and neurological abnormalities and growth retardation are induced (1)(2)(3).…”

Alteration of mitochondrial DNA and RNA level in human fibroblasts with impaired vitamin B12 coenzyme synthesis

“…Disorders of Cbl metabolism may affect mitochondrial (mt) functions. Methylmalonyl and propionic acid accumulation has been claimed to cause a reduction of pyruvate dehydrogenase, succinate dehydrogenase and succinyl‐CoA ligase activities and a reduction in cell ATP content [3–6]. The energetic metabolism might also be impaired by the accumulation of saturated and unsaturated monocarboxylic fatty acids, as a result of ketotic episodes of organic acidemia [7].…”

Biochemistry, function, and deficiency of vitamin B12 in Caenorhabditis elegans

“…18 Thus, holo-MCM activity was very low during B 12 deficiency and then significant accumulation of MMA occurs in the cells. 47 MMA is a potent inhibitor of succinate dehydrogenase (EC 1.3.99.1) that participates in both the TCA cycle and respiratory chain. 48 Thus, MMA increase due to B 12 deficiency blocks the mitochondrial respiration and consequently disrupts various metabolic pathways.…”