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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: |
Lareau, C.A.  ORCID: https://orcid.org/0000-0003-4179-4807, Dubois, S.M. ORCID: https://orcid.org/0000-0002-3169-2893, Buquicchio, F.A., Hsieh, Y.H. ORCID: https://orcid.org/0000-0003-3037-8728, Garg, K., Kautz, P. ORCID: https://orcid.org/0000-0002-9658-1676, Nitsch, L. ORCID: https://orcid.org/0000-0003-0775-1969, Praktiknjo, S.D. ORCID: https://orcid.org/0000-0002-0186-5271, Maschmeyer, P. ORCID: https://orcid.org/0000-0002-1705-5302, Verboon, J.M., Gutierrez, J.C., Yin, Y. ORCID: https://orcid.org/0000-0002-2220-005X, Fiskin, E., Luo, W., Mimitou, E.P. ORCID: https://orcid.org/0000-0001-9737-6394, Muus, C., Malhotra, R., Parikh, S., Fleming, M.D. ORCID: https://orcid.org/0000-0003-0948-4024, Oevermann, L., Schulte, J. ORCID: https://orcid.org/0000-0003-0671-1201, Eckert, C., Kundaje, A. ORCID: https://orcid.org/0000-0003-3084-2287, Smibert, P. ORCID: https://orcid.org/0000-0003-0772-1647, Vardhana, S.A. ORCID: https://orcid.org/0000-0002-3100-1298, Satpathy, A.T. ORCID: https://orcid.org/0000-0002-5167-537X, Regev, A. ORCID: https://orcid.org/0000-0003-3293-3158, Sankaran, V.G. ORCID: https://orcid.org/0000-0003-0044-443X, Agarwal, S. ORCID: https://orcid.org/0000-0003-4910-3118 and Ludwig, L.S. ORCID: https://orcid.org/0000-0002-2916-2164
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| 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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