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<p>Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated <i>POLG</i><sup><i>D274A</i></sup> knock-in HEK293 cell lines to introduce two metrics—single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)—to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual <i>POLG</i><sup><i>D274A</i></sup> cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.</p>

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Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月16日

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  • Yu-Hsin Hsieh,
  • Pauline Kautz,
  • Lena Nitsch,
  • Ambre M. Giguelay,
  • Janet Liebold,
  • Veronika Dimitrova,
  • Stephania Contreras Castillo,
  • Freya Jungen,
  • Gabor Zsurka,
  • Genevieve Trombly,
  • Markus Schuelke,
  • Wolfram S. Kunz,
  • Caleb A. Lareau,
  • Leif S. Ludwig

摘要

Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics—single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)—to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.