Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells Journal Article
| Authors: | 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.; Ludwig, L. S. |
| Article Title: | Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells |
| 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. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | controlled study; protein expression; human cell; gene deletion; genetics; mutation; cd8+ t lymphocyte; t lymphocyte; phenotype; cd34 antigen; erythroid precursor cell; erythropoiesis; in vivo study; in vitro study; stem cell; chromatin; quantitative analysis; hematopoietic stem cell; lymphoid progenitor cell; dna, mitochondrial; mitochondria; cell metabolism; myeloid progenitor cell; mitochondrion; immunocompetent cell; peripheral blood mononuclear cell; mitochondrial dna; oocyte development; disorders of mitochondrial functions; mitochondrial diseases; plasmacytoid dendritic cell; mitochondrial dna disorder; mitochondrial genome; purifying selection; humans; human; article; heteroplasmy; protein fingerprinting; multiomics; mitochondrial genetics |
| Journal Title: | Nature Genetics |
| Volume: | 55 |
| Issue: | 7 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-07-01 |
| Start Page: | 1198 |
| End Page: | 1209 |
| Language: | English |
| DOI: | 10.1038/s41588-023-01433-8 |
| PUBMED: | 37386249 |
| PROVIDER: | scopus |
| PMCID: | PMC10548551 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
