دورية أكاديمية
Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
| العنوان: | Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes. |
|---|---|
| المؤلفون: | Kim M; Tri-Institutional PhD Program in Computational Biology & Medicine, Weill Cornell Medicine, New York City, NY, USA.; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Gorelick AN; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Vàzquez-García I; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Williams MJ; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Salehi S; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Shi H; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Weiner AC; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Ceglia N; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Funnell T; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Park T; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Boscenco S; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., O'Flanagan CH; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Jiang H; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Grewal D; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Tang C; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Rusk N; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Gammage PA; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Beatson Institute, Glasgow, UK., McPherson A; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Aparicio S; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Shah SP; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. shahs3@mskcc.org., Reznik E; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. reznike@mskcc.org. |
| المصدر: | Nature genetics [Nat Genet] 2024 May; Vol. 56 (5), pp. 889-899. Date of Electronic Publication: 2024 May 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| مواضيع طبية MeSH: | DNA, Mitochondrial*/genetics , Single-Cell Analysis*/methods , Genome, Mitochondrial* , DNA Copy Number Variations*/genetics , Cell Nucleus*/genetics , Neoplasms*/genetics , Neoplasms*/pathology, Humans ; Cell Line, Tumor ; Animals ; Mitochondria/genetics ; Whole Genome Sequencing/methods ; Mice ; Heteroplasmy/genetics |
| مستخلص: | 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. (© 2024. The Author(s).) |
| References: | Reznik, E. et al. Mitochondrial DNA copy number variation across human cancers. eLife 5, e10769 (2016). (PMID: 26901439477522110.7554/eLife.10769) Yuan, Y. et al. Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nat. Genet. 52, 342–352 (2020). (PMID: 32024997705853510.1038/s41588-019-0557-x) Gaude, E. et al. NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction. Mol. Cell 69, 581–593 (2018). (PMID: 29452638582397310.1016/j.molcel.2018.01.034) Vyas, S., Zaganjor, E. & Haigis, M. C. Mitochondria and cancer. Cell 166, 555–566 (2016). (PMID: 27471965503696910.1016/j.cell.2016.07.002) Shidara, Y. et al. Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res. 65, 1655–1663 (2005). (PMID: 1575335910.1158/0008-5472.CAN-04-2012) Park, J. S. et al. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum. Mol. Genet. 18, 1578–1589 (2009). (PMID: 19208652273381610.1093/hmg/ddp069) Gorelick, A. N. et al. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat. Metab. 3, 558–570 (2021). (PMID: 33833465930498510.1038/s42255-021-00378-8) Filograna, R. et al. Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse. Sci. Adv. 5, eaav9824 (2019). (PMID: 30949583644738010.1126/sciadv.aav9824) Stewart, J. B. & Chinnery, P. F. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 16, 530–542 (2015). (PMID: 2628178410.1038/nrg3966) Wei, W. et al. Germline selection shapes human mitochondrial DNA diversity. Science 364, eaau6520 (2019). (PMID: 3112311010.1126/science.aau6520) Chinnery, P. F., Samuels, D. C., Elson, J. & Turnbull, D. M. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 1323–1325 (2002). (PMID: 1241422510.1016/S0140-6736(02)11310-9) Kang, E. et al. Age-related accumulation of somatic mitochondrial DNA mutations in adult-derived human iPSCs. Cell Stem Cell 18, 625–636 (2016). (PMID: 2715145610.1016/j.stem.2016.02.005) Ludwig, L. S. et al. Lineage tracing in humans enabled by mitochondrial mutations and single-cell genomics. Cell 176, 1325–1339 (2019). (PMID: 30827679640826710.1016/j.cell.2019.01.022) Lareau, C. A. et al. Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling. Nat. Biotechnol. 39, 451–461 (2020). (PMID: 32788668787858010.1038/s41587-020-0645-6) Miller, T. E. et al. Mitochondrial variant enrichment from high-throughput single-cell RNA-seq resolves clonal populations. Nat. Biotechnol. 40, 1030–1034 (2021). (PMID: 10.1038/s41587-022-01210-8) Xu, J. et al. Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA. eLife 8, e45105 (2019). (PMID: 30958261646992610.7554/eLife.45105) Jiang, M. et al. Increased total mtDNA copy number cures male infertility despite unaltered mtDNA mutation load. Cell Metab. 26, 429–436 (2017). (PMID: 2876818010.1016/j.cmet.2017.07.003) Grady, J. P. et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol. Med. 10, e8262 (2018). (PMID: 29735722599156410.15252/emmm.201708262) Salehi, S. et al. Clonal fitness inferred from time-series modelling of single-cell cancer genomes. Nature 595, 585–590 (2021). (PMID: 34163070839607310.1038/s41586-021-03648-3) Funnell, T. et al. Single-cell genomic variation induced by mutational processes in cancer. Nature 612, 106–115 (2022). (PMID: 36289342971211410.1038/s41586-022-05249-0) Laks, E. et al. Clonal decomposition and DNA replication states defined by scaled single-cell genome sequencing. Cell 179, 1207–1221 (2019). (PMID: 31730858691216410.1016/j.cell.2019.10.026) Ju, Y. S. et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3, e02935 (2014). (PMID: 25271376437185810.7554/eLife.02935) Burr, S. P. & Chinnery, P. F. Measuring single-cell mitochondrial DNA copy number and heteroplasmy using digital droplet polymerase chain reaction. J. Vis. Exp., https://doi.org/10.3791/63870 (2022). (PMID: 10.3791/6387035913155) Müller-Höcker, J. et al. Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes. Am. J. Pathol. 184, 2922–2935 (2014). (PMID: 2541847410.1016/j.ajpath.2014.07.015) Cree, L. M. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 40, 249–254 (2008). (PMID: 1822365110.1038/ng.2007.63) Reber, S. & Goehring, N. W. Intracellular scaling mechanisms. Cold Spring Harb. Perspect. Biol. 7, a019067 (2015). (PMID: 26254310466507310.1101/cshperspect.a019067) Rafelski, S. M. et al. Mitochondrial network size scaling in budding yeast. Science 338, 822–824 (2012). (PMID: 23139336360241610.1126/science.1225720) Miettinen, T. P. & Björklund, M. Cellular allometry of mitochondrial functionality establishes the optimal cell size. Dev. Cell 39, 370–382 (2016). (PMID: 27720611510469310.1016/j.devcel.2016.09.004) Miettinen, T. P. & Björklund, M. Mitochondrial function and cell size: an allometric relationship. Trends Cell Biol. 27, 393–402 (2017). (PMID: 2828446610.1016/j.tcb.2017.02.006) D’Erchia, A. M. et al. Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity. Mitochondrion 20, 13–21 (2015). (PMID: 2544639510.1016/j.mito.2014.10.005) Basu, A., Lenka, N., Mullick, J. & Avadhani, N. G. Regulation of murine cytochrome oxidase Vb gene expression in different tissues and during myogenesis. Role of a YY-1 factor-binding negative enhancer. J. Biol. Chem. 272, 5899–5908 (1997). (PMID: 903820810.1074/jbc.272.9.5899) Seel, A. et al. Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth. Nat. Struct. Mol. Biol. 30, 1549–1560 (2023). (PMID: 376795641058469310.1038/s41594-023-01091-8) Osman, C., Noriega, T. R., Okreglak, V., Fung, J. C. & Walter, P. Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. Proc. Natl Acad. Sci. USA 112, E947–E956 (2015). (PMID: 25730886435281910.1073/pnas.1501737112) Galitski, T., Saldanha, A. J., Styles, C. A., Lander, E. S. & Fink, G. R. Ploidy regulation of gene expression. Science 285, 251–254 (1999). (PMID: 1039860110.1126/science.285.5425.251) Comai, L. The advantages and disadvantages of being polyploid. Nat. Rev. Genet. 6, 836–846 (2005). (PMID: 1630459910.1038/nrg1711) Soto, I. et al. Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes. Genome Biol. 23, 170 (2022). (PMID: 35945592936152210.1186/s13059-022-02732-9) Couvillion, M. T., Soto, I. C., Shipkovenska, G. & Churchman, L. S. Synchronized mitochondrial and cytosolic translation programs. Nature 533, 499–503 (2016). (PMID: 27225121496428910.1038/nature18015) Lazarou, M., McKenzie, M., Ohtake, A., Thorburn, D. R. & Ryan, M. T. Analysis of the assembly profiles for mitochondrial- and nuclear-DNA-encoded subunits into complex I. Mol. Cell. Biol. 27, 4228–4237 (2007). (PMID: 17438127190004610.1128/MCB.00074-07) Gyorfy, M. F. et al. Nuclear–cytoplasmic balance: whole genome duplications induce elevated organellar genome copy number. Plant J. 108, 219–230 (2021). (PMID: 10.1111/tpj.15436) Pica-Mattoccia, L. & Attardi, G. Expression of the mitochondrial genome in HeLa cells. IX. Replication of mitochondrial DNA in relationship to cell cycle in HeLa cells. J. Mol. Biol. 64, 465–484 (1972). (PMID: 502318410.1016/0022-2836(72)90511-6) Antes, A. et al. Differential regulation of full-length genome and a single-stranded 7S DNA along the cell cycle in human mitochondria. Nucleic Acids Res. 38, 6466–6476 (2010). (PMID: 20530535296522810.1093/nar/gkq493) Chatre, L. & Ricchetti, M. Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle. Nucleic Acids Res. 41, 3068–3078 (2013). (PMID: 23345615359768110.1093/nar/gkt015) Sasaki, T., Sato, Y., Higashiyama, T. & Sasaki, N. Live imaging reveals the dynamics and regulation of mitochondrial nucleoids during the cell cycle in Fucci2-HeLa cells. Sci. Rep. 7, 11257 (2017). (PMID: 28900194559580910.1038/s41598-017-10843-8) McInnes, L., Healy, J. & Astels, S. Hdbscan: hierarchical density based clustering. J. Open Source Softw. 2, 205 (2017). (PMID: 10.21105/joss.00205) Campbell, K. R. et al. clonealign: statistical integration of independent single-cell RNA and DNA sequencing data from human cancers. Genome Biol. 20, 54 (2019). (PMID: 30866997641714010.1186/s13059-019-1645-z) Yang, S. Y. et al. Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease. Genome Res. 31, 349–358 (2021). (PMID: 33441415791944810.1101/gr.269381.120) Gupta, R. et al. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 620, 839–848 (2023). (PMID: 375873381044725410.1038/s41586-023-06426-5) Nekhaeva, E. et al. Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues. Proc. Natl Acad. Sci. USA 99, 5521–5526 (2002). (PMID: 1194386012280210.1073/pnas.072670199) Herbst, A. et al. Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. J. Gerontol. A Biol. Sci. Med. Sci. 62, 235–245 (2007). (PMID: 1738972010.1093/gerona/62.3.235) Mahmood, M. et al. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat. Cancer. https://doi.org/10.1038/s43018-023-00721-w (2024). De Grey, A. D. A proposed refinement of the mitochondrial free radical theory of aging. Bioessays 19, 161–166 (1997). (PMID: 904624610.1002/bies.950190211) Shigenaga, M. K., Hagen, T. M. & Ames, B. N. Oxidative damage and mitochondrial decay in aging. Proc. Natl Acad. Sci. USA 91, 10771–10778 (1994). (PMID: 79719614510810.1073/pnas.91.23.10771) DeHaan, C. et al. Mutation in mitochondrial complex I ND6 subunit is associated with defective response to hypoxia in human glioma cells. Mol. Cancer 3, 19 (2004). (PMID: 1524889648108210.1186/1476-4598-3-19) Kollberg, G., Moslemi, A.-R., Lindberg, C., Holme, E. & Oldfors, A. Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I. J. Neuropathol. Exp. Neurol. 64, 123–128 (2005). (PMID: 1575122610.1093/jnen/64.2.123) Sazanov, L. A Structural Perspective on Respiratory Complex I: Structure and Function of NADH:Ubiquinone Oxidoreductase (Springer Science & Business Media, 2012). Chae, J. H. et al. A novel ND3 mitochondrial DNA mutation in three Korean children with basal ganglia lesions and complex I deficiency. Pediatr. Res. 61, 622–624 (2007). (PMID: 1741387310.1203/pdr.0b013e3180459f2d) O’Hara, R. et al. Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution. Genome Res. 29, 1878–1888 (2019). (PMID: 31548359683673110.1101/gr.250480.119) Schmoller, K. M. & Skotheim, J. M. The biosynthetic basis of cell size control. Trends Cell Biol. 25, 793–802 (2015). (PMID: 26573465677327010.1016/j.tcb.2015.10.006) Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011). (PMID: 21221095334618210.1038/nbt.1754) Vázquez-García, I. et al. Ovarian cancer mutational processes drive site-specific immune evasion. Nature 612, 778–786 (2022). (PMID: 36517593977181210.1038/s41586-022-05496-1) Shi, H. et al. Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells. Nat. Commun. 15, 2482 (2024). (PMID: 385091111095474110.1038/s41467-024-46710-0) Weiner, A. C. et al. Single-cell DNA replication dynamics in genomically unstable cancers. Preprint at bioRxiv https://doi.org/10.1101/2023.04.10.536250 (2023). Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). (PMID: 23945592377639010.1038/nature12477) Lai, D., Ha, G., & Shah, S. HMMcopy: Copy number prediction with correction for GC and mappability bias for HTS data. HMMcopy, R package version 1.44.0 https://doi.org/doi:10.18129/B9.bioc.HMMcopy (2023). Kwok, A. W. C. et al. MQuad enables clonal substructure discovery using single cell mitochondrial variants. Nat. Commun. 13, 1205 (2022). (PMID: 35260582890444210.1038/s41467-022-28845-0) Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018). (PMID: 29608179670074410.1038/nbt.4096) Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019). (PMID: 31178118668739810.1016/j.cell.2019.05.031) Zhang, A. W. et al. Probabilistic cell-type assignment of single-cell RNA-seq for tumor microenvironment profiling. Nat. Methods 16, 1007–1015 (2019). (PMID: 31501550748559710.1038/s41592-019-0529-1) Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019). (PMID: 31740819688469310.1038/s41592-019-0619-0) Pencina, M. J. & D'Agostino, R. B. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat. Med. 23, 2109–2123 (2004). (PMID: 1521160610.1002/sim.1802) Benedetti, E. et al. A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation. Nat. Metab. 5, 1029–1044 (2023). (PMID: 373371201029095910.1038/s42255-023-00817-8) Therneau, T. M., Lumley, T., Elizabeth, A. & Cynthia, C. survival: survival analysis. R version 3.2-3. CRAN.R-project.org/package=survival (2022). Kim, M. Single cell mtDNA dynamics in tumors is driven by co-regulation of nuclear and mitochondrial genomes. Zenodo 10.5281/zenodo.10498239 (2024). Kim, M. et al. mtdna dlp. GitHub github.com/reznik-lab/mtdna-dlp (2024). |
| معلومات مُعتمدة: | SAC220206 Susan G. Komen (Susan G. Komen Breast Cancer Foundation); R37 CA276200 United States CA NCI NIH HHS; W81XWH-18-1-0318 U.S. Department of Defense (United States Department of Defense); RM1 HG011014 United States HG NHGRI NIH HHS; R37-CA276200 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); RM1-HG011014 U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI); P30 CA008748 United States CA NCI NIH HHS; P30-CA008748 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) |
| تواريخ الأحداث: | Date Created: 20240513 Date Completed: 20240516 Latest Revision: 20240520 |
| رمز التحديث: | 20240521 |
| مُعرف محوري في PubMed: | PMC11096122 |
| DOI: | 10.1038/s41588-024-01724-8 |
| PMID: | 38741018 |
| قاعدة البيانات: | MEDLINE |
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