Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration
Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration
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DOI：
10.1016/j.bbamcr.2016.11.029
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发表时间：
2017-02-01
影响因子：
5.1
通讯作者：
Grossman, Lawrence I.
中科院分区：
文献类型：
--
作者：
Aras, Siddhesh;Arrabi, Hassan;Grossman, Lawrence I.
我们以前表明，MNRR 1（线粒体核逆行调节因子1，也CHCHD 2）在两个亚细胞区室中发挥作用，在每个区室中显示不同的功能。在线粒体中，它是结合细胞色素c氧化酶（考克斯）的呼吸应激调节剂，而在细胞核中，它是COX 412和其他缺氧刺激基因的反式激活因子。我们现在表明，酪氨酸-99的磷酸化促进了MRR 1与考克斯的结合，并且这种相互作用刺激了呼吸。我们发现，磷酸化的MNRR 1发生在线粒体和介导的ARG 2激酶（ARG）。一个具有夸大表型的Charcot-Marie-Tooth病1A型家族在MNRR 1中存在Q112 H突变，该突变位于MNRR 1转录激活所必需的结构域中。此外，突变导致蛋白质在线粒体中响应细胞应激而发挥次优功能。Q112 H突变阻碍了蛋白质与Abl激酶相互作用的能力，导致缺陷的酪氨酸磷酸化和由此产生的呼吸缺陷。(C)© 2016 Elsevier B. V.版权所有。
We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX412 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG). A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1. Furthermore, the mutation causes the protein to function suboptimally in the mitochondria in response to cellular stress. The Q112H mutation hinders the ability of the protein to interact with Abl kinase, leading to defective tyrosine phosphorylation and a resultant defect in respiration. (C) 2016 Elsevier B.V. All rights reserved.