Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
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线粒体DNA疾病的单细胞多组学研究揭示了人类免疫细胞中纯化选择的动态变化。
DOI：
10.1038/s41588-023-01433-8
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发表时间：
2023-07
期刊：
影响因子：
30.8
通讯作者：
Ludwig, Leif S.
中科院分区：
文献类型：
--
作者：
Lareau, Caleb A.;Dubois, Sonia M.;Buquicchio, Frank A.;Hsieh, Yu-Hsin;Garg, Kopal;Kautz, Pauline;Nitsch, Lena;Praktiknjo, Samantha D.;Maschmeyer, Patrick;Verboon, Jeffrey M.;Gutierrez, Jacob C.;Yin, Yajie;Fiskin, Evgenij;Luo, Wendy;Mimitou, Eleni P.;Muus, Christoph;Malhotra, Rhea;Parikh, Sumit;Fleming, Mark D.;Oevermann, Lena;Schulte, Johannes;Eckert, Cornelia;Kundaje, Anshul;Smibert, Peter;Vardhana, Santosha A.;Satpathy, Ansuman T.;Regev, Aviv;Sankaran, Vijay G.;Agarwal, Suneet;Ludwig, Leif S.
线粒体DNA(MtDNA)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有关，这表明了不同的器官和细胞类型的代谢脆弱性。在这里，我们建立了一种多组学方法来量化来自六个患者的单个细胞中mtDNA的缺失以及细胞状态特征，跨越单个大规模mtDNA缺失(SLSMD)的表型谱。通过对206,663细胞的分析，我们揭示了致病线粒体DNA缺失异质性的动态变化，与体内T细胞状态的纯化选择和明显的代谢脆弱性一致，并在体外验证了这些观察结果。通过将分析扩展到造血祖细胞和红系祖细胞，我们揭示了mtDNA动力学和特定细胞类型的基因调节适应，证明了干扰线粒体基因组完整性的上下文依赖性。总而言之，我们报告了不同谱系的个体血液和免疫细胞的致病mtDNA异质性动力学，展示了单细胞多组学在揭示线粒体遗传学基本特性方面的力量。
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.
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影响因子：
3.7
作者：
Enns GM;Moore T;Le A;Atkuri K;Shah MK;Cusmano-Ozog K;Niemi AK;Cowan TM
通讯作者：
Cowan TM
影响因子：
4.5
作者：
Basu S;Xie X;Uhler JP;Hedberg-Oldfors C;Milenkovic D;Baris OR;Kimoloi S;Matic S;Stewart JB;Larsson NG;Wiesner RJ;Oldfors A;Gustafsson CM;Falkenberg M;Larsson E
通讯作者：
Larsson E
影响因子：
48
作者：
Korsunsky, Ilya;Millard, Nghia;Raychaudhuri, Soumya
通讯作者：
Raychaudhuri, Soumya
影响因子：
30.8
作者：
Krishnan, Kim J.;Reeve, Amy K.;Turnbull, Doug M.
通讯作者：
Turnbull, Doug M.
影响因子：
5.2
作者：
Cherry, Anne B. C.;Gagne, Katelyn E.;Mcloughlin, Erin M.;Baccei, Anna;Gorman, Bryan;Hartung, Odelya;Miller, Justine D.;Zhang, Jin;Zon, Rebecca L.;Ince, Tan A.;Neufeld, Ellis J.;Lerou, Paul H.;Fleming, Mark D.;Daley, George Q.;Agarwal, Suneet
通讯作者：
Agarwal, Suneet