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Deciphering the role of amino acid transporters in mitochondrial myopathy

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
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-20 至 2023-08-31

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中文摘要
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英文摘要
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.
期刊论文(5)
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科研奖励(0)
会议论文
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
影响因子: --
作者: [Wang,Xun, Mishra,Prashant]
通讯作者: Mishra,Prashant
DOI: 10.1038/s43587-021-00164-x
发表时间: 2022
期刊: Nature aging
影响因子: --
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
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
Deciphering the role of amino acid transporters in mitochondrial myopathy
  • 批准号:
    9788032
  • 项目类别:
  • 资助金额:
    $35.64万
  • 财政年份:
    2018
  • 负责人:
    Prashant Mishra
  • 依托单位:
Deciphering the role of amino acid transporters in mitochondrial myopathy
  • 批准号:
    10232080
  • 项目类别:
  • 资助金额:
    $34.57万
  • 财政年份:
    2018
  • 负责人:
    Prashant Mishra
  • 依托单位:
海外基金