June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Non-random cellular distribution of the mitochondrial 3243A>G variant in the human retina and choroid and its impact on disease phenotype.
Author Affiliations & Notes
  • Nathaniel Kevin Mullin
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Andrew P Voigt
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Miles J Flamme-Wiese
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Xiuying Liu
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Kelsey L Wieland
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Edwin M Stone
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Budd A. Tucker
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Robert F Mullins
    University of Iowa Institute for Vision Research, Iowa, United States
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, United States
  • Footnotes
    Commercial Relationships   Nathaniel Mullin None; Andrew Voigt None; Miles Flamme-Wiese None; Xiuying Liu None; Kelsey Wieland None; Edwin Stone None; Budd Tucker None; Robert Mullins None
  • Footnotes
    Support  NIH Grant GM008629, NIH Grant GM139776, NIH Grant EY025580
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2654. doi:
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    • Get Citation

      Nathaniel Kevin Mullin, Andrew P Voigt, Miles J Flamme-Wiese, Xiuying Liu, Kelsey L Wieland, Edwin M Stone, Budd A. Tucker, Robert F Mullins; Non-random cellular distribution of the mitochondrial 3243A>G variant in the human retina and choroid and its impact on disease phenotype.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2654.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The dynamics of mitochondrial genome partitioning in complex tissues such as the retina have implications for how mitochondrial variants cause disease. In this study, we sought to understand how the most common pathogenic mitochondrial variant (m.3243A>G) is distributed across ocular cell types in eyes from patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and how this distribution relates to gene expression in ocular cells. We hypothesized that in the eyes of MELAS patients with severe retinal atrophy, the photoreceptors and retinal pigment epithelium (RPE) would harbor high levels of m.3243G.

Methods : We profiled the proportion of the m.3243A>G variant in single cells from the retina, RPE, and choroid of a MELAS patient, as well as from a healthy control donor. Chromatin accessibility and heteroplasmy were assessed using the mitochondrial single-cell assay for transposable chromatin by sequencing (mt-scATACseq), which captures both nuclear and mitochondrial DNA reads. The transcriptomes of single cells from the same samples were profiled in parallel using single-cell RNA sequencing (scRNAseq). Data were analyzed using Seurat and Signac in R.

Results : We find that the proportion of the pathogenic m.3243G allele is neither evenly nor randomly distributed among ocular cell types. While all classes of neural retinal cells and the RPE exhibited a high degree of heteroplasmy, endothelial and lymphocyte populations of the choroid are near homoplasmic for the wildtype m.3243A allele. Single cell gene expression analysis reveals that the presence of the m.3243G allele in neural retinal cells deranges expression of pathways involved in energy metabolism and the response to oxidative stress. However, many of the same pathways in choroidal cell classes homoplasmic for the wildtype allele are also dysregulated.

Conclusions : This work illuminates the non-random segregation of a pathogenic mitochondrial variant in the retina and choroid and demonstrates that the m.3243A>G variant causes non-cell autonomous tissue dysfunction in the complex and metabolically linked light sensing tissue of the eye. Expanding our understanding of the mechanisms that underlie the non-random partitioning of m.3243A>G will enhance management of this and potentially other mitochondrial diseases.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Overview of experimental approach.

Overview of experimental approach.

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