Inhibition of succinate dehydrogenase and β‐hydroxybutyrate dehydrogenase activities by methylmalonate in brain and liver of developing rats

Abstract

The effects of methylmalonate (MMA) on succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase (HBDH) activities in brain and liver of 15-day-old rats were studied. The apparent Km of SDH for succinate was 0.45 mmol/L in brain and 0.34 mmol/L in liver. MMA inhibited the enzyme activity in both tissues with Ki values of 4.5 mmol/L and 2.3 mmol/L in brain and liver, respectively, and the inhibition was of the reversible competitive type. The calculated Km for HBDH with beta-hydroxybutyrate as substrate was 1.26 mmol/L in brain and 0.36 mmol/L in liver. MMA inhibited the enzyme with a Ki value of 0.015 mmol/L in brain and 0.275 mmol/L in liver. These results are probably relevant to our understanding of cerebral metabolism in methylmalonic acidaemic children, especially during ketoacidotic and hypoglycaemic crises, and may be related to the pathogenesis of cerebral dysfunction of methylmalonic acidaemia.

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

“…Since our data did not confirm the results of a previous study using PMS (12), we systematically investigated modulatory factors of complex II activity. Complex II activity reached a maximum at pH 7.4 (V max (mean of n ϭ 8 experiments): 1.05 units/mg protein), whereas pH changes dramatically reduced V max (given as units/mg protein: pH 5, 0.03; pH 6, 0.28; pH 7, 1.02; pH 8, 0.7; pH 9, 0.11; pH 10, 0.01).…”

“…The previous demonstrations that MA competitively inhibits complex II (19) and that MCA blocks the TCA cycle (34) corroborate our notion MMAinduced cell damage is mediated via intracellular formation of these two compounds rather than by direct inactivation of complex II by MMA. This is further supported by the fact that PMS, which has been used as electron mediator in the above mentioned studies (11,12), is more reactive than DBQ, being oxidized by O 2 and H 2 O 2 to pyocyanine (35). Thus, PMS is at risk to be unspecifically inactivated as electron mediator under certain conditions.…”

“…In particular, MMA-induced inhibition of complex II (succinate dehydrogenase, EC 1.3.99.1), which is imparted in the TCA cycle and the mitochondrial respiratory chain, has become a focus of interest (12). MMA induces cell damage in different neuronal culture systems (13,14).…”

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

“…MMA, 1 which reaches millimolar concentrations in body fluids and brain tissue during acute metabolic crises, was first suggested to act as an endogenous toxic metabolite, mediating neuronal damage via inhibition of mitochondrial energy metabolism (10,11). It has been hypothesized that MMA induced inhibition of complex II (synonym, succinate:ubiquinone oxidoreductase), a multiprotein assembly imparted in the tricarboxylic acid cycle and the mitochondrial respiratory chain, has become a focus of interest (12).…”

Expanding the Spectrum of Methylmalonic Acid-Induced Pallidal Stroke: First Reported Case of Metabolic Globus Pallidus Stroke in Transcobalamin II Deficiency

“…Cobalamin ultimately has an important role in the metabolism of both homocysteine and methylmalonic acid as a cofactor for methionine synthase and methylmalonyl-CoA mutase, respectively (Takahashi-Iñiguez et al 2012;Banerjee and Ragsdale 2003). MethylmalonylCoA mutase isomerizes mitochondrial methylmalonyl-CoA to succinyl-CoA, a crucial substrate in energy provision via the citric acid cycle and complex II of the respiratory chain (Dutra et al 1993;Okun et al 2002). Inherited deficiency of TCII has been described in over 40 patients (Watkins and Rosenblatt 2011).…”