Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency.
Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency.
复制标题
抑制ATR会逆转线粒体呼吸不足。
DOI：
10.3390/cells11111731
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发表时间：
2022-05-24
期刊：
影响因子：
6
通讯作者：
Rea, Shane L.
中科院分区：
文献类型：
--
作者：
Borror, Megan B.;Girotti, Milena;Kar, Adwitiya;Cain, Meghan K.;Gao, Xiaoli;MacKay, Vivian L.;Herron, Brent;Bhaskaran, Shylesh;Becerra, Sandra;Novy, Nathan;Ventura, Natascia;Johnson, Thomas E.;Kennedy, Brian K.;Rea, Shane L.
关键词：
影响线粒体电子传递链（ETC）的疾病通常表现为阈值效应障碍，这意味着患者只有在达到一定水平的ETC功能障碍时才会出现症状。细胞可以调用机制来避免达到其关键的ETC阈值，但识别这些过程是一个持续的挑战。在线虫秀丽隐杆线虫中，线粒体ETC活性的严重降低会缩短寿命，但轻度降低实际上会延长寿命，这为确定阈值规避机制提供了机会。在这里，我们表明，去除ATL-1，而不是ATM-1，ATR和ATM的蠕虫直系同源物，分别是人类细胞中关键的核DNA损伤检查点蛋白，出乎意料地减轻了ETC功能障碍的严重程度。多项遗传和生化测试显示，没有证据表明暴露于ETC破坏的动物突变或DNA断裂增加。降低的ETC功能反而改变了核糖核苷酸池和脱氧核糖核苷酸池中的核苷酸比率，并导致RNA聚合酶停滞，这也是已知的激活ATR。出乎意料的是，atl-1突变体面临线粒体ETC破坏维持正常水平的耗氧量，并有一个翻译核糖体的丰度增加。这表明ATL-1的检查点信号传导通常抑制细胞质翻译。综上所述，我们的数据表明，ETC不足的C。elegans导致核苷酸失衡，导致RNA聚合酶停滞、ATL-1活化、整体翻译抑制和ETC功能障碍放大。ATL-1的缺失有效地逆转了ETC破坏的严重性，使得动物在表型上变得更接近野生型。
Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is reached. Cells can invoke mechanisms to circumvent reaching their critical ETC threshold, but it is an ongoing challenge to identify such processes. In the nematode Caenorhabditis elegans, severe reduction of mitochondrial ETC activity shortens life, but mild reduction actually extends it, providing an opportunity to identify threshold circumvention mechanisms. Here, we show that removal of ATL-1, but not ATM-1, worm orthologs of ATR and ATM, respectively, key nuclear DNA damage checkpoint proteins in human cells, unexpectedly lessens the severity of ETC dysfunction. Multiple genetic and biochemical tests show no evidence for increased mutation or DNA breakage in animals exposed to ETC disruption. Reduced ETC function instead alters nucleotide ratios within both the ribo- and deoxyribo-nucleotide pools, and causes stalling of RNA polymerase, which is also known to activate ATR. Unexpectedly, atl-1 mutants confronted with mitochondrial ETC disruption maintain normal levels of oxygen consumption, and have an increased abundance of translating ribosomes. This suggests checkpoint signaling by ATL-1 normally dampens cytoplasmic translation. Taken together, our data suggest a model whereby ETC insufficiency in C. elegans results in nucleotide imbalances leading to the stalling of RNA polymerase, activation of ATL-1, dampening of global translation, and magnification of ETC dysfunction. The loss of ATL-1 effectively reverses the severity of ETC disruption so that animals become phenotypically closer to wild type.
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影响因子：
16
作者：
Heo JM;Livnat-Levanon N;Taylor EB;Jones KT;Dephoure N;Ring J;Xie J;Brodsky JL;Madeo F;Gygi SP;Ashrafi K;Glickman MH;Rutter J
通讯作者：
Rutter J
影响因子：
14.9
作者：
Guilliam TA;Keen BA;Brissett NC;Doherty AJ
通讯作者：
Doherty AJ
ATR在线粒体上扮演直接的抗凋亡作用，该抗凋亡作用受Prolyl异构酶PIN1的调节。
影响因子：
16
作者：
Hilton BA;Li Z;Musich PR;Wang H;Cartwright BM;Serrano M;Zhou XZ;Lu KP;Zou Y
通讯作者：
Zou Y
DOI：
10.1016/s0197-2456(98)00037-3
发表时间：
1998-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Dupont, WD;Plummer, WD
通讯作者：
Plummer, WD
影响因子：
2.9
作者：
Bhaskaran, Shylesh;Butler, Jeffrey A.;Rea, Shane L.
通讯作者：
Rea, Shane L.