Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT)

Four members of the SLC16A gene family encode classical monocarboxylate transporters MCT1-4. Widely expressed, they all function as proton-dependent transporters of monocarboxylic acids such as lactate and pyruvate and ketone bodies such as acetacetate and beta-hydroxybutyrate. These processes are crucial in the regulation of energy metabolism and acid-base homeostasis.<br><br>SLC16A1 encodes MCT1, a ubiquitiously expressed protein. Heterozygous defects in SLC16A1 were found in patients with symptomatic deficiency in lactate transport (SDLT aka erythrocyte lactate transporter defect; MIM:245340), resulting in an acidic intracellular environment and muscle degeneration with the release of myoglobin and creatine kinase (Merezhinskaya et al. 2000). This defect could compromise extreme performance in otherwise healthy individuals.<br><br>SLC16A1 is essential for lactate transport in muscle cells. It is also highly enriched in astrocytes and oligodendroglia, neuroglia that support, insulate and provide energy metabolites to axons. Oligodendroglia dysfunction can lead to axon degeneration in several diseases. The cause is unknown but disruption of SLC16A1 transporter produces axon damage and neuron loss in animal and cell culture models. In humans, this transporter is reduced in patients with amyotrophic lateral sclerosis (Lee et al. 2012).<br><br>In cancer cells, a common change is the upregulation of glycolysis. The anti-cancer drug candidate 3-bromopyruvate (3-BrPA) can inhibit glycolysis through its uptake into cancer cells via SLC16A1 so it is the main determinant of 3-BrPA sensitivity in these cells (Birsoy et al. 2013).

SLC16A基因家族的四个成员编码经典的单羧酸转运蛋白MCT1-4。这些蛋白表达广泛，均作为依赖于质子的单羧酸（如乳酸、丙酮酸）和酮体（如乙酰乙酯、β-羟基丁酸）的转运蛋白。这些过程对于调节能量代谢和酸碱平衡至关重要。<br><br>SLC16A1编码MCT1，这是一种在体内普遍表达的蛋白。SLC16A1的杂合子突变在乳酸转运缺陷（SDLT，即红细胞乳酸转运蛋白缺陷；MIM:245340）的患者中发现，导致细胞内环境酸性化以及肌红蛋白和肌酸激酶的释放，进而引起肌肉退行性变（Merezhinskaya等，2000年）。这种缺陷可能损害健康个体的极限性能。<br><br>SLC16A1对于肌肉细胞中的乳酸转运至关重要。它在星形胶质细胞和小胶质细胞中高度富集，这些神经胶质细胞支持、绝缘和为轴突提供能量代谢物。小胶质细胞功能障碍可导致多种疾病中的轴突退行性变。其原因尚不明确，但SLC16A1转运蛋白的破坏在动物和细胞培养模型中会导致轴突损伤和神经元损失。在人类中，这种转运蛋白在肌萎缩侧索硬化症（ALS）患者中减少（Lee等，2012年）。<br><br>在癌细胞中，糖酵解的上调是一种常见的改变。抗癌药物候选物3-溴丙酸（3-BrPA）可以通过其通过SLC16A1进入癌细胞来抑制糖酵解，因此它是这些细胞3-BrPA敏感性的主要决定因素（Birsoy等，2013年）。