Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.
PLoS Biol. 2024 Aug 22;22(8):e3002723. doi: 10.1371/journal.pbio.3002723. eCollection 2024 Aug.
The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.
线粒体 DNA 向真核生物核基因组的转移（Numts）与非人类物种的寿命有关，最近有研究表明这种转移在人类中也会以罕见的方式在一代与下一代之间发生。在这里，我们通过两种方式研究了人类的 Numt 发生动力学。首先，我们定量分析了来自不同个体的 1187 个死后大脑和血液样本中的 Numts。与循环免疫细胞（n=389）相比，有丝分裂后组织（n=798）中的 Numts 更多，这与它们潜在的体细胞积累一致。在大脑样本中，与小脑样本相比，背外侧前额叶皮层（DLPFC）中的体细胞 Numt 插入物富集了 5.5 倍，这表明大脑 Numts 是在发育过程中或在整个生命过程中自发产生的。此外，Numts 数量的增加与更早的死亡率有关。与寿命更长的个体相比，没有认知障碍（NCI）的个体在年轻时死亡的大脑每失去十年寿命，大约携带 2 个以上的 Numts。其次，我们使用重复测量全基因组测序设计在人类成纤维细胞模型中测试了 Numt 的动态转移，该模型再现了衰老的几个分子特征。这些纵向实验显示，每 13 天左右就会逐渐积累 1 个 Numt。Numt 发生与大规模基因组不稳定性无关，也不太可能由细胞克隆性驱动。靶向药理学干扰，包括慢性糖皮质激素信号或破坏线粒体氧化磷酸化（OxPhos），仅适度增加 Numt 发生的速度，而表现出线粒体 DNA 不稳定性的患者来源 SURF1 突变细胞比健康供体积累 Numts 的速度快 4.7 倍。综合来看，我们的数据记录了人类细胞中的自发 Numt 发生，并证明了大脑皮质体细胞 Numts 与人类寿命之间存在关联。这些发现为人类有丝分裂后组织之间的线粒体-核水平基因转移在以前认为的更短时间尺度上产生具有功能相关性的人类 Numts 提供了可能性。
