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MtDNA transfer dynamics in vivo can induce dose-dependent tumor cell dedifferentiation and heterogeneity

ABSTRACT: Tumor heterogeneity limits treatment efficacy and drives therapy resistance. Although mitochondrial genome (mtDNA) mutations occur in ~60% of solid tumors, their contribution to heterogeneity is unexplored. We deployed established rho0 B16 melanoma and 4T1 breast cancer mouse models and engineered isogenic tumor cells carrying unique homoplasmic single-nucleotide mtDNA variants used as tracking barcodes. Using single-cell ATAC-seq with mitochondrial genotyping (mtscATAC-seq / mgatk) and single-cell multiome (ATAC + gene expression) profiling, we mapped and quantified horizontal mtDNA exchange within tumors in vivo. Respiration-deficient mutant tumor cells selectively and stably acquired host mtDNA, and mtDNA transfer induced dose-dependent tumor cell dedifferentiation and heterogeneity.

ORGANISM(S): Mus musculus

PROVIDER: GSE338956 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:Mitochondria generate over 90% of the cellular energy and are central to health and disease. Mitochondrial DNA (mtDNA) heteroplasmy represents a significant source of cellular genetic diversity and has been shown to cause impaired mitochondrial function and even mitochondrial diseases. However, mitochondrial genetic heterogeneity across different human cell types at the population level is poorly understood. Here we present scMOCHA, a scalable computational framework that resolves high-confidence, single-cell resolution mtDNA heteroplasmy directly from standard single-cell RNA sequencing (scRNA-seq) data. Applying scMOCHA to all publicly available human peripheral blood mononuclear cells (PBMC) and bone marrow (BM) scRNA-seq datasets comprising 5.5 million cells, we uncover the single-cell landscape of mtDNA single-nucleotide variants (SNVs) and heteroplasmy levels in the human hematopoietic system across ages and cell types, including previously unreported SNVs and recurrent somatic hotspot SNVs in unrelated individuals. PBMCs and BM share many inherited homoplasmic and highly heteroplasmic SNVs but few somatic SNVs. Somatic SNVs are tissue- and cell type-specific and distributed across the mtDNA genome, suggesting that they arise in a largely random fashion. Although mtDNA replication error is the most likely dominant force shaping homoplasmic variants, oxidative stress may drive a significant portion of heteroplasmic and somatic mutations in the mtDNA genome. Importantly, we discover cell type-specific and human disease-associated mtDNA SNVs. By coupling mtDNA genotypes with matched single-cell nuclear transcriptomes and structural modeling, we uncover potential molecular mechanisms of how these disease-associated mtDNA SNVs impact cellular function such as inflammation and contribute to disease. Together, these findings define the single-cell variant landscape of the human mitochondrial genome and reveal previously unrecognized lineage- and disease-associated patterns of mtDNA variation in the human hematopoietic system.

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MtDNA transfer dynamics in vivo can induce dose-dependent tumor cell dedifferentiation and heterogeneity

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