학술논문
Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells
Document Type
Original Paper
Author
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.
Source
Nature Genetics. 55(7):1198-1209
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
Abstract
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.
Single-cell analyses of immune cells from patients with pathogenic, single large-scale mitochondrial DNA (mtDNA) deletions including Pearson syndrome describe heteroplasmy dynamics consistent with purifying selection, as well as T-cell state-specific regulatory mechanisms and metabolic vulnerabilities.
Single-cell analyses of immune cells from patients with pathogenic, single large-scale mitochondrial DNA (mtDNA) deletions including Pearson syndrome describe heteroplasmy dynamics consistent with purifying selection, as well as T-cell state-specific regulatory mechanisms and metabolic vulnerabilities.