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Methylmalonic Acid Inhibits Respiration in Rat Liver Mitochondria¹

Department of Applied Biological Chemistry, University of Osaka Prefecture, Sakai, Osaka 593, Japan ^* Department of Foods and Nutrition, Kochi Women's University, Kochi 780, Japan

Methylmalonic acid (MMA), which accumulates and is excreted in urine in mammals during vitamin B-12 deficiency, has been reported to inhibit succinate dehydrogenase, an enzyme involved in the mitochondrial tricarboxylic acid (TCA) cycle in rat liver. The enzyme inhibition by MMA may lead to various metabolic disorders as well as inhibition of mitochondrial energy generation in vitamin B-12-deficient mammals. To clarify the inhibition of succinate dehydrogenase by MMA in intact rat liver mitochondria, the effect of MMA on mitochondrial respiration was studied. When 6 mmol/L MMA was added to the reaction mixture for measuring mitochondrial respiration with succinate as a substrate, MMA was taken up and accumulated by the mitochondria (34–53 mmol/L). The accumulation of mitochondrial MMA was stimulated by the addition of ADP. Methylmalonic acid competitively inhibited State 3 mitochondrial respiration, and the K_i for the acid was 4.2 ± 0.4 mmol/L. Although the respiratory control ratio decreased with increasing MMA concentration, the acid did not affect the phosphorus/oxygen ratio. Mitochondrial MMA accumulation secondary to vitamin B-12 deficiency inhibits succinate dehydrogenase and may contribute to various metabolic disorders associated with vitamin B-12 deficiency.

KEY WORDS: • vitamin B-12 • methylmalonic acid • mitochondrial respiration • rats

¹ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

² Current address: Division of Drug Safety Evaluation, Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima 772, Japan.

³ To whom correspondence should be addressed.

Manuscript received 8 March 1995. Revision accepted 10 July 1995.

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