MAINTENANCE OF MITOCHONDRIAL PROTEIN FOLDING AS AN AGING EFFECTOR

项目摘要 线粒体功能随着年龄的增长而下降，在帕金森氏症等疾病中会加剧。 线粒体衰退的一个潜在原因是有害线粒体的繁殖。 基因组(MtDNA)贯穿生物体的整个生命周期，就像在个体肌肉中观察到的那样 细胞或多巴胺能神经元。线粒体DNA只编码呼吸链和三磷酸腺苷合成酶 这些成分和损伤导致氧化磷酸化(OxPhos)缺乏。因为 线粒体DNA存在于每个细胞100s-1000s的拷贝数中，单个基因组中的病变是很好的耐受性。 然而，如果有害基因组积累到超过60%，与 OXPHOS功能障碍随之而来，包括细胞退化和死亡。目前还不清楚是如何 有害的线粒体DNA被维护，它们是如何传播的，最终为什么它们是有毒的。 细胞对OxPhos缺乏做出反应的一种机制是激活线粒体 未折叠蛋白反应(UPRmt)，启动线粒体修复和恢复计划。 我们发现，UPRmt激活可提供保护，防止由以下原因引起的OxPhos缺陷 OxPhos基因的核突变或抗细菌衍生毒素(铜绿假单胞菌产生 例如氰化物)。我们令人惊讶的初步数据表明，UPRMT被要求 在线虫异质性模型中维持和繁殖有害的mtDNA。因此，我们 假设有害的mtDNA是自私的，或寄生的，并利用 制定内源性应激反应计划，以修复和应对线粒体功能障碍。 在这里，我们计划研究UPRmt激活和有害的mtDNA的后果 繁殖是与年龄相关的线粒体功能障碍的一个因素。

Project Summary Mitochondrial function declines with age and is exacerbated in disease states such as Parkinson's. One potential cause of the mitochondrial decline is the propagation of deleterious mitochondrial genomes (mtDNAs) throughout an organism's lifetime as has been observed in individual muscle cells or dopaminergic neurons. mtDNAs only encode respiratory chain and ATP synthase components and thus lesions result in oxidative phosphorylation (OxPhos) deficiency. Because mtDNAs exist at 100s-1000s of copies per cell, a lesion in a single genome is well tolerated. However, if the deleterious genome accumulates to greater than ~60%, pathology related to OxPhos dysfunction ensues including cell degeneration and death. It is currently unclear how deleterious mtDNAs are maintained, how they are propagated and ultimately why they are toxic. One mechanism by which cells respond to OxPhos deficiency is by activating the mitochondrial unfolded protein response (UPRmt), which initiates a mitochondrial repair and recovery program. We have found that UPRmt activation provides protection against OxPhos deficiencies caused by nuclear mutations in OxPhos genes or against bacterial derived toxins (P. aeruginosa produces cyanide for example). Our surprising preliminary data indicate that the UPRmt is required to maintain and propagate deleterious mtDNAs in a C. elegans model of heteroplasmy. Therefore, we hypothesize that deleterious mtDNAs are selfish, or parasitic, and take advantage of an endogenous stress response program in place to repair and respond to mitochondrial dysfunction. Here, we plan to examine the consequences of UPRmt activation and deleterious mtDNA propagation as a contributor to age-associated mitochondrial dysfunction.