ArticleCell2025
Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Harnessing mitochondrial genome editing for crop improvement: principles and applications.aBIOTECH · 2026Review
- Hypertensive mt. tRNARedox biology · 2026Article
- UVA Irradiation Promotes ROS-Mediated Formation of the Common Deletion in Mitochondrial DNA.Life (Basel, Switzerland) · 2026Article
- MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.Nature structural & molecular biology · 2026Article
- Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.Nature communications · 2026Article
- Targeting organelle function in T cells for cancer immunotherapy.Nature reviews. Immunology · 2026Review
- Article
- Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.Journal of translational medicine · 2025Review
- Functional dominance in the central dogma of tumor mitochondrial genetics.Nature genetics · 2025Article
- Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.Nature genetics · 2025Article
- Shaping Precision Medicine: The Journey of Sequencing Technologies Across Human Solid Tumors.Biomedicines · 2025Review
- MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.BMC genomics · 2025Article
- Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.EMBO reports · 2025Review
- Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system.NAR molecular medicine · 2025Article
- Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
21 authors.
Funding
Abstract
Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.