Deciphering the role of amino acid transporters in mitochondrial myopathy

破译氨基酸转运蛋白在线粒体肌病中的作用

• 批准号: 10458552
• 负责人: Prashant Mishra
• 金额: $ 35.28万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458552
• 关键词: Affect; Alleles; Amino Acid Transporter; Amino Acids; Animal Diseases; Animals; Carbon; Carbon Isotopes; Catabolism; Cell membrane; Cells; Complement; Cultured Cells; Defect; Deletion Mutation; Diet; Disease; Disease Progression; Engineering; Excision; Family; Family member; Functional disorder; Glucose; Glutamates; Glutamine; Goals; Health; Homeostasis; Impairment; Individual; Investigation; Isotopes; Knock-out; Lead; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Myopathies; Molecular; Motor; Mus; Muscle; Muscle function; Mutation; Myopathy; Nutrient; Organelles; Outcome; Oxidative Phosphorylation; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiology; Plasma; Prognosis; Role; Route; Secondary to; Severities; Skeletal Muscle; Stable Isotope Labeling; System; Techniques; Testing; Tissues; Up-Regulation; Work; amino acid metabolism; body system; design; glucose metabolism; human disease; improved; in vivo; member; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mitochondrial metabolism; mouse model; muscle physiology; muscular system; mutant; new therapeutic target; novel; novel therapeutics; oxidation; response; skeletal disorder; skeletal muscle metabolism; solute; targeted treatment; therapy development

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.

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， 线粒体功能障碍的设置，但鲜为人知的是，在患病的代谢途径的活动， 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。

项目成果

A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle.

线粒体融合蛋白 2/HIF1α 轴在骨骼肌再生过程中设置了成熟检查点。

• DOI: 10.1172/jci161638
• 发表时间: 2022-12-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Wang, Xun;Jia, Yuemeng;Zhao, Jiawei;Lesner, Nicholas P.;Menezes, Cameron J.;Shelton, Spencer D.;Venigalla, Siva Sai Krishna;Xu, Jian;Cai, Chunyu;Mishra, Prashant
• 通讯作者: Mishra, Prashant

Fusion of dysfunction muscle stem cells with myofibers induces sarcopenia in mice.

功能障碍的肌肉干细胞与肌纤维的融合会诱发小鼠肌肉减少症。

• DOI: 10.1101/2023.01.20.524967
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Wang,Xun;Mishra,Prashant
• 通讯作者: Mishra,Prashant

Scinderin promotes fusion of electron transport chain dysfunctional muscle stem cells with myofibers.

• DOI: 10.1038/s43587-021-00164-x
• 发表时间: 2022
• 期刊: Nature aging
• 作者: Wang X;Shelton SD;Bordieanu B;Frank AR;Yi Y;Venigalla SSK;Gu Z;Lenser NP;Glogauer M;Chandel NS;Zhao H;Zhao Z;McFadden DG;Mishra P
• 通讯作者: Mishra P

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.

致病性线粒体 DNA 突变抑制黑色素瘤转移。

• DOI: 10.1101/2023.09.01.555986
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Shelton,SpencerD;House,Sara;Ramesh,Vijayashree;Chen,Zhenkang;Wei,Tao;Wang,Xun;Llamas,ClaireB;Venigalla,SivaSaiKrishna;Menezes,CameronJ;Zhao,Zhiyu;Gill,JenniferG;DeBerardinis,RalphJ;Morrison,SeanJ;Tasdogan,Alpaslan;Mishr
• 通讯作者: Mishr

Differential requirements for mitochondrial electron transport chain components in the adult murine liver.

• DOI: 10.7554/elife.80919
• 发表时间: 2022-09-26
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lesner NP;Wang X;Chen Z;Frank A;Menezes CJ;House S;Shelton SD;Lemoff A;McFadden DG;Wansapura J;DeBerardinis RJ;Mishra P
• 通讯作者: Mishra P