A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels.
A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels.
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DOI：
10.1016/j.celrep.2014.03.065
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发表时间：
2014-05-08
期刊：
影响因子：
8.8
通讯作者：
MacKeigan JP
中科院分区：
文献类型：
--
作者：
Lanning NJ;Looyenga BD;Kauffman AL;Niemi NM;Sudderth J;DeBerardinis RJ;MacKeigan JP
改变的细胞生物能量学和线粒体功能是包括癌症、糖尿病和神经退行性疾病在内的几种疾病的主要特征。鉴于这种与人类健康的重要联系，我们试图定义线粒体内对维持体内稳态ATP水平至关重要的蛋白质。我们筛选了一个靶向> 1，000个核编码基因的RNAi文库，这些基因的蛋白质产物在多种代谢条件下定位于线粒体，以检查它们对细胞ATP水平的影响。我们确定了一种机制，通过这种机制，糖酵解条件下的电子传递链扰动通过增强糖酵解通量来增加ATP的产生，从而突出了细胞代谢可塑性的潜力。此外，我们鉴定了一种线粒体腺苷酸激酶（AK4），其调节细胞ATP水平、AMPK信号传导，并且其表达与神经胶质瘤患者存活率显著相关。因此，这项研究在不同代谢底物的背景下绘制了> 1，000种线粒体蛋白的生物能量景观，并开始将关键代谢基因与临床结果联系起来。
Altered cellular bioenergetics and mitochondrial function are major features of several diseases including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions to examine their effect on cellular ATP levels. We identified a mechanism by which electron transport chain perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux; thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels, AMPK signaling, and whose expression significantly correlates with glioma patient survival. As a result, this study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
4.8
作者：
Hao, Wenshan;Chang, Chao-Pei Betty;Xu, Jun
通讯作者：
Xu, Jun
影响因子：
3.8
作者：
Edhager, Anders V.;Stenbroen, Vibeke;Palmfeldt, Johan
通讯作者：
Palmfeldt, Johan
影响因子：
9.9
作者：
Greenberg, Anthony J.;Hackett, Sean R.;Clark, Andrew G.
通讯作者：
Clark, Andrew G.
影响因子：
2.9
作者：
Hopper, RK;Carroll, S;Balaban, RS
通讯作者：
Balaban, RS