Massively parallel sequencing of mitochondrial genome in primary open angle glaucoma identifies somatically acquired mitochondrial mutations in ocular tissue

Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open an...

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Vydáno v:	Scientific reports Ročník 14; číslo 1; s. 26324 - 12
Hlavní autoři:	Vallabh, Neeru Amrita, Lane, Brian, Simpson, David, Fuchs, Marc, Choudhary, Anshoo, Criddle, David, Cheeseman, Robert, Willoughby, Colin
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.11.2024 Nature Publishing Group Nature Portfolio
Témata:	631/208 631/208/2489 692/699/3161/3169 692/699/3161/3172 Aged DNA biosynthesis DNA damage DNA sequencing DNA, Mitochondrial - genetics Eye diseases Female Fibroblasts Fibroblasts - metabolism Fibroblasts - pathology Genome, Mitochondrial Genomes Glaucoma Glaucoma, Open-Angle - genetics Heteroplasmy High-Throughput Nucleotide Sequencing Humanities and Social Sciences Humans Leukocytes Male Massively parallel sequencing Middle Aged Mitochondria - genetics Mitochondrial DNA Mitochondrial genome multidisciplinary Mutation Neurodegeneration Optic nerve Pathogenesis Peripheral blood Retinal ganglion cells Science Science (multidisciplinary) Somatic mutations Tenon’s fibroblasts Whole genome sequencing Tenon’s fibroblasts Glaucoma Massively parallel sequencing Mitochondrial DNA Somatic mutations Mitochondrial genome
ISSN:	2045-2322, 2045-2322
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Shrnutí:	Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open angle glaucoma (POAG). All previous mitochondrial genome sequencing studies in POAG analyzed mitochondrial DNA (mtDNA) isolated from peripheral blood leukocytes and have not evaluated cells derived from ocular tissue, which better represent the glaucomatous disease context. In this study, we evaluated mitochondrial genome variation and heteroplasmy using massively parallel sequencing of mtDNA in a cohort of patients with POAG, and in a subset assess the role of somatic mitochondrial genome mutations in disease pathogenesis using paired samples of peripheral blood leukocytes and ocular tissue (Tenon’s ocular fibroblasts). An enrichment of potentially pathogenic nonsynonymous mtDNA variants was identified in Tenon’s ocular fibroblasts from participants with POAG. The absence of oxidative DNA damage and predominance of transition variants support the concept that errors in mtDNA replication represent the predominant mutation mechanism in Tenon’s ocular fibroblasts from patients with POAG. Pathogenic somatic mitochondrial genome mutations were observed in people with POAG. This supports the role of somatic mitochondrial genome variants in the etiology of glaucoma.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-72684-6