Deciphering the role of amino acid transporters in mitochondrial myopathy

项目摘要 线粒体在营养物质转化为能量的过程中起着核心作用，因此，对这一过程的破坏 细胞器导致营养分解代谢的改变。骨骼肌系统受到明显的影响 线粒体功能障碍的背景，但对疾病患者代谢途径的活动知之甚少 肌肉组织。我们的初步工作发现，培养的人的中枢碳代谢发生了变化 具有致病线粒体基因组(MtDNA)突变的细胞，并确定了关键成员的变化 调节这些扰动的溶质输运载体(SLC)家族。重要的是，类似的变化在 SLC家族成员，特别是XC-转运系统，存在于慢性阻塞性肺疾病患者的肌肉组织中 线粒体肌病。利用线粒体疾病的小鼠模型，我们提出了三个具体目标 描述XC-在改变患病骨骼肌代谢流中的作用。在目标1中，我们将 使用稳定同位素标记技术表征患病动物的代谢途径。这些结果 将量化突变肌肉组织的体内新陈代谢，提供差异的详细图谱 在正常状态和疾病状态之间。在目标2中，我们将研究XC-在调节骨骼肌中的作用 新陈代谢，利用可用的敲除等位基因。在目标3中，我们将检验以下假设：改变XC- 活动通过跟踪活体肌肉的生理和功能来调节患病小鼠的疾病进展 动物。总之，这些目标将量化线粒体肌病的代谢变化，并与 它们对活体肌肉的功能和健康有好处。这一结果有可能确定新的靶向治疗方法 碳代谢，这可能对患有线粒体肌病的患者有益。

Project Summary Mitochondria are centrally involved in the conversion of nutrients into energy, and thus, damage to this organelle results in altered nutrient catabolism. The skeletal muscle system is prominently affected in the setting of mitochondrial dysfunction, but little is known regarding the activity of metabolic pathways in diseased muscular tissue. Our preliminary work has discovered that central carbon metabolism is altered in cultured cells with pathogenic mitochondrial genome (mtDNA) mutations, and identified alterations in key members of the solute transport carrier (SLC) family which regulate these perturbations. Importantly, similar alterations in SLC family members, particularly the xc- transport system, occur in muscular tissues of subjects with mitochondrial myopathy. Using mouse models of mitochondrial disease, we propose three specific aims to characterize the role of xc- in altering metabolic fluxes in diseased skeletal muscle. In Aim 1, we will characterize metabolic pathways in diseased animals using stable isotope labeling techniques. These results will quantitate in vivo metabolism in mutant muscle tissue, providing a detailed mapping of the differences between normal and diseased states. In Aim 2, we will investigate the role of xc- in regulating skeletal muscle metabolism, making use of an available knockout allele. In Aim 3, we will test the hypothesis that altering xc- activity modulates disease progression in diseased mice, by following muscular physiology and function in live animals. Together, these aims will quantitate metabolic alterations in mitochondrial myopathies, and relate them to in vivo muscle function and health. The results have the potential to identify new therapies targeting carbon metabolism which may be beneficial for patients suffering from mitochondrial myopathies.