PDF(Pubmed)
Abstract：
Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer\'s disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.
摘要：
线粒体呼吸链（RC）功能需要数十种蛋白质之间的化学计量相互作用，但它们的共同调节尚未在人脑中定义。这里,使用三个独立队列的定量蛋白质组学,我们系统地表征了人背外侧前额叶皮质(DLPFC)线粒体RC蛋白的共调控模式.而物理组装成稳定复合物的RC蛋白质亚基的丰度是相关的，表明他们的共同监管，RC装配因素表现出适度的共同调节。在复杂的I中，与线粒体(mt)DNA编码的亚基相比,核DNA编码的亚基表现出>2.5倍的共调。此外，mtDNA拷贝数与mtDNA编码的亚基丰度无关，表明mtDNA含量不是限制性的。阿尔茨海默病（AD）大脑表现出减少的复杂IRC亚基丰度，这一效应主要是由线粒体蛋白质含量总体降低2-4%驱动的。这些发现为确定与年龄和疾病相关的人脑线粒体功能侵蚀的分子机制提供了基础知识。
