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


  • 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


  • Nature Genetics


  • Nat Genet 55 (7): 1198-1209


  • 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.