研究揭示人血液中mtDNA突变与年龄相关积累的机制
研究揭示人血液中mtDNA突变与年龄相关积累的机制
作者： 小柯机器人 发布时间：2026/5/28 20:24:49
本期文章：《自然》：Online/在线发表
近日，美国麻省理工学院和哈佛大学的布罗德研究所教授Vamsi K. Mootha及其团队研制了人血液中mtDNA突变与年龄相关积累的机制。这一研究成果于2026年5月27日发表在国际顶尖学术期刊《自然》上。
在这里，研究小组通过调用人类血液主题全基因组序列中的mtDNA序列、mtDNA丰度和mtDNA异质变异来研究潜在的机制。课题组人员观察到，mtDNA单核苷酸变异（mtSNVs）在60岁时急剧积累，发生在低水平的异质性中，几乎没有证据表明正选择，并且可能主要是中性的。mtSNVs的突变谱并不像通常所说的那样反映氧化损伤，而是与mtDNA复制错误更一致。
为了理解为什么mtSNV会随着年龄的增长而被检测到，研究组对异质mtSNV负担进行了全基因组关联研究，确定了TERT、TCL1A和SMC4附近的种系变异，所有这些变异都与克隆造血（CH）2有关。罕见变异分析还表明，高mtSNV负荷与许多CH驱动基因的突变有关。即使在排除了已知CH驱动突变的个体后，这些遗传关联仍然存在。
他们的结果支持一种模型，即“隐性”mtDNA突变最初作为复制错误随机出现，但无法大量检测到。只有随着血液中细胞克隆的年龄增长，它们才会变得明显。小组认为mtDNA的高拷贝数和突变率使其成为CH引起的体细胞嵌合的敏感血液标记物。他们的工作从机制上统一了衰老的三个突出特征：TERT、CH的常见种系变异和mtDNA突变的累积。
据悉，突变线粒体DNA （mtDNA）异质性的积累是衰老的最强标志之一。
附：英文原文
Title: Mechanism of age-related accumulation of mtDNA mutations in human blood
Author: Gupta, Rahul, Durham, Timothy J., Chau, Grant, Kanai, Masahiro, Uddin, Md Mesbah, Lu, Wenhan, Argentieri, M. Austin, Karczewski, Konrad J., Howrigan, Daniel, Natarajan, Pradeep, Zhou, Wei, Neale, Benjamin M., Mootha, Vamsi K.
Issue&Volume: 2026-05-27
Abstract: Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which ‘cryptic’ mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
DOI: 10.1038/s41586-026-10569-6
Source: https://www.nature.com/articles/s41586-026-10569-6