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Abstract
BackgroundSubstantially elevated blood D-lactate (DLA) concentrations are associated with neurocardiac toxicity in humans and animals. The neurological symptoms are similar to inherited or acquired abnormalities of pyruvate metabolism. We hypothesized that DLA interferes with mitochondrial utilization of L-lactate and pyruvate in brain and heart.MethodsRespiration rates in rat brain, heart and liver mitochondria were measured using DLA, LLA and pyruvate independently and in combination.ResultsIn brain mitochondria, state 3 respiration was 53% and 75% lower with DLA as substrate when compared with LLA and pyruvate, respectively (p < 0.05). Similarly in heart mitochondria, state 3 respiration was 39% and 86% lower with DLA as substrate when compared with LLA or pyruvate, respectively (p < 0.05). However, state 3 respiration rates were similar between DLA, LLA and pyruvate in liver mitochondria. Combined incubation of DLA with LLA or pyruvate markedly impaired state 3 respiration rates in brain and heart mitochondria (p < 0.05) but not in liver mitochondria. DLA dehydrogenase activities were 61% and 51% lower in brain and heart mitochondria compared to liver, respectively, whereas LLA dehydrogenase activities were similar across all three tissues. An LDH inhibitor blocked state 3 respiration with LLA as substrate in all three tissues. A monocarboxylate transporter inhibitor blocked respiration with all three substrates.ConclusionsDLA was a poor respiratory substrate in brain and heart mitochondria and inhibited LLA and pyruvate usage in these tissues. Further studies are warranted to evaluate whether these findings support, in part, the possible neurological and cardiac toxicity caused by high DLA levels.
Highlights
Lactate exists as two stereoisomers, L-lactate and D-lactate
Pyruvate generated during glycolysis is transported into the mitochondria via monocarboxylate transporters (MCTs) MCT1 [17]
The objectives of this study were to compare the mitochondrial utilization of D-lactate to L-lactate and pyruvate in mitochondria from rat heart, liver and brain tissues
Summary
Lactate exists as two stereoisomers, L-lactate and D-lactate. Under healthy physiological conditions, L-lactate is the major enantiomer found in blood whereas D-lactate is normally present in very low concentrations [1]. Supra-physiological levels of D-lactate have been found in several disease states such as diarrhea, short bowel syndrome, and diabetes [2,3]. Most research in this area focus on the cause and the consequences of extremely high levels of D-lactate (> 3 mM D-lactate in plasma, resulting in D-lactic acidosis) in the body [3,4,5,6,7]. Pyruvate breakdown irreversibly funnels the products of glycolysis into the Krebs cycle to produce ATP and a large quantity of NADH [12]. We hypothesized that DLA interferes with mitochondrial utilization of L-lactate and pyruvate in brain and heart
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