Inhibition of brain energy metabolism by the α-keto acids accumulating in maple syrup urine disease

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Abstract

Neurological dysfunction is a common finding in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly known. In the present study, we investigated the effect of the in vitro effect of the branched chain α-keto acids (BCKA) accumulating in MSUD on some parameters of energy metabolism in cerebral cortex of rats. [14CO2] production from [14C] acetate, glucose uptake and lactate release from glucose were evaluated by incubating cortical prisms from 30-day-old rats in Krebs–Ringer bicarbonate buffer, pH 7.4, in the absence (controls) or presence of 1–5 mM of α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV) or α-ketoisovaleric acid (KIV). All keto acids significantly reduced 14CO2 production by around 40%, in contrast to lactate release and glucose utilization, which were significantly increased by the metabolites by around 42% in cortical prisms. Furthermore, the activity of the respiratory chain complex I–III was significantly inhibited by 60%, whereas the other activities of the electron transport chain, namely complexes II, II–III, III and IV, as well as succinate dehydrogenase were not affected by the keto acids. The results indicate that the major metabolites accumulating in MSUD compromise brain energy metabolism by blocking the respiratory chain. We presume that these findings may be of relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.

Keywords

Maple syrup urine disease
α-Ketoisocaproic acid
α-Keto-β-methylvaleric acid
α-Ketoisovaleric acid
Energy metabolism

Abbreviations

MSUD
maple syrup urine disease
BCAA
branched chain amino acids
BCKA
branched chain keto acids
BCKAD
branched chain l-α-keto acid dehydrogenase
KIC
α-ketoisocaproic acid
KMV
α-keto-β-methylvaleric acid
KIV
α-ketoisovaleric acid
CNS
central nervous system
GABA
gamma-aminobutyric acid

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