Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline

Antioxidants

Luigi Donato¹  Concetta Scimone¹  Simona Alibrandi¹  Rosalia D’Angelo¹  Antonina Sidoti¹  Federica Scalia²  Alessandro Pitruzzella² 

[1] Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy;Department of Biomedicine Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy;

关键词: Mitochondria;    mtDNA;    RNA-Seq;    Retinal degenerations;    VUS;   

DOI  :  10.3390/antiox9111158

来源: DOAJ

【 摘 要 】

Mitochondria are subject to continuous oxidative stress stimuli that, over time, can impair their genome and lead to several pathologies, like retinal degenerations. Our main purpose was the identification of mtDNA variants that might be induced by intense oxidative stress determined by N-retinylidene-N-retinylethanolamine (A2E), together with molecular pathways involving the genes carrying them, possibly linked to retinal degeneration. We performed a variant analysis comparison between transcriptome profiles of human retinal pigment epithelial (RPE) cells exposed to A2E and untreated ones, hypothesizing that it might act as a mutagenic compound towards mtDNA. To optimize analysis, we proposed an integrated approach that foresaw the complementary use of the most recent algorithms applied to mtDNA data, characterized by a mixed output coming from several tools and databases. An increased number of variants emerged following treatment. Variants mainly occurred within mtDNA coding sequences, corresponding with either the polypeptide-encoding genes or the RNA. Time-dependent impairments foresaw the involvement of all oxidative phosphorylation complexes, suggesting a serious damage to adenosine triphosphate (ATP) biosynthesis, that can result in cell death. The obtained results could be incorporated into clinical diagnostic settings, as they are hypothesized to modulate the phenotypic expression of mtDNA pathogenic variants, drastically improving the field of precision molecular medicine.

【 授权许可】

Unknown