Department of Pathology, Stanford University, Stanford, CA, USA.
Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA.
Nat Genet. 2023 Jul;55(7):1198-1209. doi: 10.1038/s41588-023-01433-8. Epub 2023 Jun 29.
Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.
线粒体 DNA（mtDNA）中的致病突变会损害细胞代谢，导致细胞异质性和疾病。不同的突变与不同的临床表型相关，表明存在不同的组织和细胞类型特异性代谢脆弱性。在这里，我们建立了一种多组学方法，以定量分析来自六个患者的单个细胞中 mtDNA 的缺失以及细胞状态特征，这些患者跨越了单个大片段 mtDNA 缺失（SLSMD）的表型谱。通过对 206633 个细胞进行分析，我们揭示了致病 mtDNA 缺失异质性的动力学，这与纯化选择一致，并在体内和体外验证了不同 T 细胞状态下的不同代谢脆弱性。通过将分析扩展到造血和红细胞祖细胞，我们揭示了 mtDNA 动力学和细胞类型特异性基因调控适应，证明了破坏线粒体基因组完整性的上下文依赖性。总的来说，我们报告了个体血液和免疫细胞在谱系中的致病性 mtDNA 异质性动力学，展示了单细胞多组学揭示线粒体遗传学基本特性的强大功能。
