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

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. and Dubois, S.M. and Buquicchio, F.A. and Hsieh, Y.H. and Garg, K. and Kautz, P. and Nitsch, L. and Praktiknjo, S.D. and Maschmeyer, P. and Verboon, J.M. and Gutierrez, J.C. and Yin, Y. and Fiskin, E. and Luo, W. and Mimitou, E.P. and Muus, C. and Malhotra, R. and Parikh, S. and Fleming, M.D. and Oevermann, L. and Schulte, J. and Eckert, C. and Kundaje, A. and Smibert, P. and Vardhana, S.A. and Satpathy, A.T. and Regev, A. and Sankaran, V.G. and 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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