Deciphering the role of amino acid transporters in mitochondrial myopathy

项目摘要 线粒体主要参与将营养物质转化为能量，因此， 细胞器导致改变的营养催化剂。骨骼肌系统受到显著影响， 线粒体功能障碍的发生，但关于疾病中代谢途径的活性知之甚少 肌肉组织我们的初步工作发现，在培养的细胞中， 致病性线粒体基因组（mtDNA）突变的细胞，并确定了关键成员的改变， 调节这些扰动的溶质转运载体（SLC）家族。重要的是， SLC家族成员，特别是xc-转运系统，出现在患有 线粒体肌病使用线粒体疾病的小鼠模型，我们提出了三个具体目标， 表征XC-在改变患病骨骼肌代谢通量中的作用。在目标1中，我们 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 将定量突变肌肉组织中的体内代谢，提供差异的详细绘图 正常和患病之间的区别在目标2中，我们将研究xc-在调节骨骼肌中的作用， 代谢，利用可用的敲除等位基因。在目标3中，我们将测试改变xc的假设- 活动调节疾病小鼠的疾病进展，通过跟踪肝脏中的肌肉生理学和功能， 动物总之，这些目标将量化线粒体肌病中的代谢改变， 他们在体内肌肉功能和健康。这些结果有可能确定新的治疗方法， 这可能有益于患有线粒体肌病的患者。

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.