Abstract：
Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.
摘要：
线粒体转运体促进代谢物在细胞质和线粒体之间的转运，并且对于线粒体功能完整性至关重要。尽管许多线粒体转运蛋白与代谢性疾病相关，它们如何调节线粒体功能及其在细胞水平上的代谢贡献在很大程度上是未知的。这里,我们显示线粒体硫胺素焦磷酸（TPP）转运蛋白SLC25A19是线粒体呼吸所必需的。SLC25A19缺乏导致细胞活力降低，综合应激反应(ISR)增加，增强糖酵解和提高细胞对2-脱氧葡萄糖（2-DG）治疗的敏感性。通过一系列的生化检测,我们发现线粒体NADH的耗竭是SLC25A19缺陷细胞线粒体呼吸受损的主要原因.我们还显示了SLC25A19参与调节复合物I和III的酶活性，三羧酸（TCA）循环，苹果酸-天冬氨酸穿梭和氨基酸代谢。始终如一，加入艾地苯醌,辅酶Q10的类似物可恢复SLC25A19缺陷细胞中的线粒体呼吸和细胞活力。一起,我们的发现为SLC25A19在线粒体和细胞生理学中的功能提供了新的见解，并提示恢复线粒体呼吸可能是治疗SLC25A19相关疾病的新策略。
