Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes Journal Article
| Authors: | Kim, M.; Gorelick, A. N.; Vàzquez-García, I.; Williams, M. J.; Salehi, S.; Shi, H.; Weiner, A. C.; Ceglia, N.; Funnell, T.; Park, T.; Boscenco, S.; O’Flanagan, C. H.; Jiang, H.; Grewal, D.; Tang, C.; Rusk, N.; Gammage, P. A.; McPherson, A.; Aparicio, S.; Shah, S. P.; Reznik, E. |
| Article Title: | Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes |
| Abstract: | The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance. © The Author(s) 2024. |
| Keywords: | controlled study; human cell; genetics; neoplasm; neoplasms; mouse; phenotype; animal; animals; mice; gene expression; genotype; pathology; cell line, tumor; tumor cell line; cell size; cell nucleus; gene dosage; dna, mitochondrial; mitochondria; mitochondrion; mitochondrial dna; dna copy number variations; copy number variation; genome, mitochondrial; single cell analysis; single-cell analysis; procedures; mitochondrial genome; cell nucleus dna; humans; human; article; whole genome sequencing; heteroplasmy; single cell rna seq |
| Journal Title: | Nature Genetics |
| Volume: | 56 |
| Issue: | 5 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-05-01 |
| Start Page: | 889 |
| End Page: | 899 |
| Language: | English |
| DOI: | 10.1038/s41588-024-01724-8 |
| PUBMED: | 38741018 |
| PROVIDER: | scopus |
| PMCID: | PMC11096122 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding authors are MSK authors: Sohrab P. Shah and Ed Reznik -- Source: Scopus |
