Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells

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Item Type:	Article
Title:	Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells
Creators Name:	Lareau, C.A., Dubois, S.M., Buquicchio, F.A., Hsieh, Y.H., Garg, K., Kautz, P., Nitsch, L., Praktiknjo, S.D., Maschmeyer, P., Verboon, J.M., Gutierrez, J.C., Yin, Y., Fiskin, E., Luo, W., Mimitou, E.P., Muus, C., Malhotra, R., Parikh, S., Fleming, M.D., Oevermann, L., Schulte, J., Eckert, C., Kundaje, A., Smibert, P., Vardhana, S.A., Satpathy, A.T., Regev, A., Sankaran, V.G., Agarwal, S. and Ludwig, L.S.
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.
Keywords:	Mitochondria, Mitochondrial DNA, Mitochondrial Diseases, Multiomics, Mutation
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	55
Number:	7
Page Range:	1198-1209
Date:	July 2023
Additional Information:	Copyright © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Official Publication:	https://doi.org/10.1038/s41588-023-01433-8
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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