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线粒体金属伴侣 SCO1 将 CTR1 维持在质膜上,以维持小鼠心脏中的铜稳态。

The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart.

机构信息

Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.

Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA.

出版信息

Hum Mol Genet. 2017 Dec 1;26(23):4617-4628. doi: 10.1093/hmg/ddx344.

Abstract

SCO1 is a ubiquitously expressed, mitochondrial protein with essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. SCO1 patients present with severe forms of early onset disease, and ultimately succumb from liver, heart or brain failure. However, the inherent susceptibility of these tissues to SCO1 mutations and the clinical heterogeneity observed across SCO1 pedigrees remain poorly understood phenomena. To further address this issue, we generated Sco1hrt/hrt and Sco1stm/stm mice in which Sco1 was specifically deleted in heart and striated muscle, respectively. Lethality was observed in both models due to a combined COX and copper deficiency that resulted in a dilated cardiomyopathy. Left ventricular dilation and loss of heart function was preceded by a temporal decrease in COX activity and copper levels in the longer-lived Sco1stm/stm mice. Interestingly, the reduction in copper content of Sco1stm/stm cardiomyocytes was due to the mislocalisation of CTR1, the high affinity transporter that imports copper into the cell. CTR1 was similarly mislocalized to the cytosol in the heart of knockin mice carrying a homozygous G115S substitution in Sco1, which in humans causes a hypertrophic cardiomyopathy. Our current findings in the heart are in marked contrast to our prior observations in the liver, where Sco1 deletion results in a near complete absence of CTR1 protein. These data collectively argue that mutations perturbing SCO1 function have tissue-specific consequences for the machinery that ultimately governs copper homeostasis, and further establish the importance of aberrant mitochondrial signaling to the etiology of copper handling disorders.

摘要

SCO1 是一种普遍表达的线粒体蛋白,在细胞色素 c 氧化酶 (COX) 组装和铜稳态调节中发挥着重要作用。SCO1 患者表现出严重的早发性疾病,最终因肝、心或脑衰竭而死亡。然而,这些组织对 SCO1 突变的固有易感性以及在 SCO1 家系中观察到的临床异质性仍然是理解不足的现象。为了进一步解决这个问题,我们分别在心脏和横纹肌中特异性缺失 Sco1 生成了 Sco1hrt/hrt 和 Sco1stm/stm 小鼠。由于 COX 和铜缺乏导致扩张型心肌病,这两种模型都观察到了致死性。在寿命较长的 Sco1stm/stm 小鼠中,左心室扩张和心脏功能丧失之前,伴随着 COX 活性和铜水平的暂时下降。有趣的是,Sco1stm/stm 心肌细胞铜含量的减少是由于 CTR1 的定位错误, CTR1 是一种将铜导入细胞的高亲和力转运体。在携带 Sco1 中 G115S 取代的纯合子的 knockin 小鼠的心脏中, CTR1 也被错误地定位到细胞质中,在人类中,这种突变会导致肥厚型心肌病。我们目前在心脏中的发现与我们之前在肝脏中的观察结果形成鲜明对比,在肝脏中,Sco1 的缺失导致 CTR1 蛋白几乎完全缺失。这些数据共同表明,突变干扰 SCO1 功能会对最终控制铜稳态的机制产生组织特异性影响,并进一步确立了异常线粒体信号对铜处理障碍病因的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b11/5886179/cdc24e2342e4/ddx344f1.jpg

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