Download Christopher Palmer Brain Energy Epub

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The brain and heart are metabolically active organs with substantial energy requirements. The major cellular pathways of energy production are glycolysis and mitochondrial oxidative phosphorylation [15]. During glycolysis, glucose is converted to pyruvate, which is accompanied by the production of ATP and NADH [15]. In mammalian cells, the enzymes responsible for pyruvate metabolism are located in the mitochondria [16]. Thus, pyruvate generated during glycolysis is transported into the mitochondria via monocarboxylate transporters (MCTs) particularly MCT1 [17]. In the mitochondria, pyruvate breakdown irreversibly funnels the products of glycolysis into the Krebs cycle to produce ATP and a large quantity of NADH [12]. NADH produced by both processes is then used to fuel mitochondrial ATP synthesis via oxidative phosphorylation or mitochondrial respiratory chain phosphorylation [15, 16].

In some tissues, L-lactate oxidation can provide cellular energy in addition to glycolysis [18, 19]. For example, L-lactate has been identified as the preferential oxidative energy substrate for the brain during excitation [20]. The Astrocyte-Neuron Lactate Shuttle hypothesis suggests that fuel for increased energy requirement of neurons during excitation is supplied by L-lactate from the surrounding astrocytes rather than glucose [18, 21]. Following its transport into the cell, cytosolic L-lactate is converted to pyruvate by L-lactate dehydrogenase (LDH), an enzyme using NAD as a cofactor [18], which subsequently enters the TCA cycle in the mitochondria for further energy production. In addition, mitochondria also contain significant amounts of LDH, located largely in the inter-membrane space [18]. L-lactate transported into the mitochondria via MCTs is metabolized to pyruvate for energy production. Therefore, mitochondrial utilization of both L-lactate and pyruvate is crucial for cellular bioenergetics.

Cellular D-lactate is metabolized by mitochondrial D-lactate dehydrogenase (DDH) using FAD as cofactor [26, 27]. The expression of DDH is tissue dependent and therefore affects the usage of D-lactate in different tissues [26, 27]. For example, due to low expression levels of DDH in the brain, the rate of oxidation of D-lactate in the brain is considerably slower compared to that of L-lactate [26, 27]. D-Lactate accumulation, then, may compromise energy metabolism by interfering with the mitochondrial usage of its more efficient energy substrates pyruvate and/or L-lactate and thus lead to toxicity. Energy deficiency in the brain of chickens has been reported following intracerebral infusion of D-lactate which suggests D-lactate's involvement in altered substrate utilization and ATP generation [28]. In this study, we hypothesized that D-lactate interferes with mitochondrial utilization of L-lactate and pyruvate.

D-lactate is present at low levels in the body and can be well utilized by the liver in both human and animal under healthy conditions [39]. However, elevated levels of blood D-lactate in several disease states [5, 40] can result in D-lactate accumulation in specific tissues and potential toxicity. In fact, high D-lactate levels are associated with neurological and cardiac dysfunction [7, 41]. The underlying mechanisms of such toxicities are not fully understood. In our study, we examined whether D-lactate was an efficient energy substrate for brain and heart mitochondrial and, if not, whether it could interfere with mitochondrial utilization of two major cellular energy substrates, L-lactate and pyruvate. Such interference could result in a cellular energy deficiency and, therefore, begin to explain, in part, the neurological and cardiac toxicities observed with D-lactic acidosis.

Interestingly, we also observed changes in oxygen uptake by pyruvate in rat heart, brain and liver mitochondria in the presence of L-lactate though the extents of inhibition were less compared to D-lactate (Table 1, 2, 3). Both D and L-lactate share the same mitochondrial membrane transporter and have the potential to competitively inhibit pyruvate transport into the mitochondria for energy production [28]. In the liver, both isomers of lactate can be recognized by mitochondrial lactate dehydrogenase (LDH and DDH respectively) and converted into pyruvate. Such conversion can therefore compensate for the reductions in pyruvate concentrations in the mitochondria resulting from inhibition of pyruvate transport into this organelle [52, 53]. However, the degree of the compensation depends on the enzyme tissue distribution and activity. In our study, DDH activities were significantly lower in rat brain and heart mitochondria compared to liver where as LDH activities were similar between all three tissues (Figure 1). The low level of DDH in rat brain and heart may explain the strong inhibition of D-lactate on mitochondrial respiration rates using pyruvate as substrate in these two tissues.

In conclusion, our study identified that D-lactate is a poor substrate for rat brain and heart mitochondria, but an efficient substrate for liver mitochondrial respiration. Low levels of DDH activity in rat brain and heart likely explain its poor utilization by mitochondria of these tissues. Additionally, D-lactate inhibited brain and heart mitochondrial respiration caused by pyruvate and L-lactate. L-Lactate also inhibited pyruvate induced mitochondrial respiration in liver, brain and heart but could maintain heart and brain mitochondrial respiration via LDH mediated conversion of L-lactate to pyruvate. Furthermore, an inhibitor of monocarboxylate transporters completely inhibited mitochondrial respiration in all tissues regardless of substrate. Collectively, these data suggest D-lactate inhibition of pyruvate and L-lactate mitochondrial utilization may be due, in part, to competitive inhibition of the monocarboxylate transporters responsible for the transport of pyruvate and lactate into the mitochondria. Since mitochondrial oxidative phosphorylation is the main source of ATP production in various tissues, disruption of mitochondrial respiratory function in brain and heart may compromise cellular energy status and result in toxicity. Hence, D-lactate mediated reductions in mitochondrial energy production may contribute to the neurological and cardiac toxicity associated with D-lactic acidosis. L-Lactic acidosis would not result in a cellular energy deficiency due to LDH mediated conversion of L-lactate to pyruvate by liver, brain, and heart mitochondria. Further investigation is warranted to determine the relationship between reductions in mitochondrial energy production to cellular energy deficiency and organ dysfunction. 59ce067264

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