Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells
Authors
- C.A. Lareau
- S.M. Dubois
- F.A. Buquicchio
- Y.H. Hsieh
- K. Garg
- P. Kautz
- L. Nitsch
- S.D. Praktiknjo
- P. Maschmeyer
- J.M. Verboon
- J.C. Gutierrez
- Y. Yin
- E. Fiskin
- W. Luo
- E.P. Mimitou
- C. Muus
- R. Malhotra
- S. Parikh
- M.D. Fleming
- L. Oevermann
- J. Schulte
- C. Eckert
- A. Kundaje
- P. Smibert
- S.A. Vardhana
- A.T. Satpathy
- A. Regev
- V.G. Sankaran
- S. Agarwal
- L.S. Ludwig
Journal
- Nature Genetics
Citation
- Nat Genet 55 (7): 1198-1209
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.