ArticleJCI insight2023
Multimodal single-cell analysis of nonrandom heteroplasmy distribution in human retinal mitochondrial disease.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 19 citations in OpenAlex.
- Article
- An Integrated Multi-omics Single Cell Atlas of the Human RPE and Choroid.bioRxiv : the preprint server for biology · 2026Article
- Single-cell Omics Assessment of Mitochondrial Function: Current Status and Future Perspectives.Genomics, proteomics & bioinformatics · 2026Review
- Single-Cell Gene Expression and eQTL Analyses in the Human Retina, RPE, and Choroid in Macular Degeneration.bioRxiv : the preprint server for biology · 2026Article
- Retinol tracing within murine neural retina reveals cell type-specific retinol transport and distribution.The Journal of clinical investigation · 2026Article
- The MTRNR2L gene family and age-related macular degeneration.Frontiers in immunology · 2026Review
- Decoding cell-class specific roles of non-coding variants in human retina.Scientific reports · 2025Article
- Melanocytes and photosensory organs share a common ancestry that illuminates the origins of the neural crest.Communications biology · 2025Article
- Prenatally derived macrophages support choroidal health and decline in age-related macular degeneration.The Journal of experimental medicine · 2025Article
- Integrating explainable machine learning and transcriptomics data reveals cell-type specific immune signatures underlying macular degeneration.NPJ genomic medicine · 2025Article
- Cell-type-specific patterns and consequences of somatic mutation in development and aging brain.bioRxiv : the preprint server for biology · 2025Article
- Article
- A rareTranslational pediatrics · 2025Article
- Retinal multimodal-imaging and functional tests in a mitochondrial disease with focal and segmental glomerulosclerosis.International journal of ophthalmology · 2025Review
- Case Report: Abnormal pupils caused by the mitochondrial MT-TL1 gene m.3243A>G mutation.Frontiers in pediatrics · 2025Article
- Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Variability of Mitochondrial DNA Heteroplasmy: Association with Asymptomatic Carotid Atherosclerosis.Biomedicines · 2024Article
- A highly reproducible and efficient method for retinal organoid differentiation from human pluripotent stem cells.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Multi-omics in exploring the pathophysiology of diabetic retinopathy.Frontiers in cell and developmental biology · 2024Review
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations observed in patients with mitochondrial disease results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored. Here, we identify nonrandom distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA-Seq, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profiled the transcriptome, chromatin accessibility state, and heteroplasmy in cells from the eyes of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and from healthy control donors. Utilizing the retina as a model for complex multilineage tissues, we found that the proportion of the pathogenic m.3243A>G allele was neither evenly nor randomly distributed across diverse cell types. All neuroectoderm-derived neural cells exhibited a high percentage of the mutant variant. However, a subset of mesoderm-derived lineage, namely the vasculature of the choroid, was near homoplasmic for the WT allele. Gene expression and chromatin accessibility profiles of cell types with high and low proportions of m.3243A>G implicate mTOR signaling in the cellular response to heteroplasmy. We further found by multimodal single-cell sequencing of retinal pigment epithelial cells that a high proportion of the pathogenic mtDNA variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings show the nonrandom nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.
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