Journal article
Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease
JCI insight, Vol.8(14), e165937
07/24/2023
DOI: 10.1172/jci.insight.165937
PMCID: PMC10443808
PMID: 37289546
Abstract
Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multi-system disease. The wide range of manifestations observed in mitochondrial disease patients 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 non-random distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA sequencing, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profile 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 healthy control donors. Utilizing the retina as a model for complex multi-lineage 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 wildtype 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 non-random nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.
Details
- Title: Subtitle
- Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease
- Creators
- Nathaniel K MullinAndrew P VoigtMiles J Flamme-WieseXiuying LiuMegan J RikerKatayoun VarzavandEdwin M StoneBudd A TuckerRobert F Mullins
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.8(14), e165937
- DOI
- 10.1172/jci.insight.165937
- PMID
- 37289546
- PMCID
- PMC10443808
- NLM abbreviation
- JCI Insight
- eISSN
- 2379-3708
- Grant note
- DOI: 10.13039/100000053, name: National Eye Institute, award: F30EY034009, P30EY025580, F30EY031923, R01EY033308; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: T32GM008629, T32GM139776; DOI: 10.13039/100001818, name: Research to Prevent Blindness, award: na; DOI: 10.13039/100012201, name: Elmer and Sylvia Sramek Charitable Trust, award: na; DOI: 10.13039/100008097, name: Edward N. and Della L. Thome Memorial Foundation, award: na
- Language
- English
- Electronic publication date
- 06/08/2023
- Date published
- 07/24/2023
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; John and Marcia Carver Nonprofit Genetic Testing Laboratory; Ophthalmology and Visual Sciences
- Record Identifier
- 9984430333702771
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