The genomic mosaic of mitochondrial dysfunction: Decoding nuclear and mitochondrial epigenetic contributions to maternally inherited diabetes and deafness pathogenesis
Luigi Donato,
Concetta Scimone,
Simona Alibrandi,
Maria Vadalà,
Massimo Castellucci,
Vincenza Maria Elena Bonfiglio,
Sergio Zaccaria Scalinci,
Giorgia Abate,
Rosalia D'Angelo,
Antonina Sidoti
Affiliations
Luigi Donato
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy; Department of Biomolecular Strategies, Genetics and Cutting-edge Therapies, I.E.ME.S.T., Palermo, 90139, Italy
Concetta Scimone
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy; Department of Biomolecular Strategies, Genetics and Cutting-edge Therapies, I.E.ME.S.T., Palermo, 90139, Italy
Simona Alibrandi
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy; Department of Biomolecular Strategies, Genetics and Cutting-edge Therapies, I.E.ME.S.T., Palermo, 90139, Italy; Corresponding author. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy.
Maria Vadalà
Department of Biomolecular Strategies, Genetics and Cutting-edge Therapies, I.E.ME.S.T., Palermo, 90139, Italy; Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), Ophthalmology Institute, University of Palermo, 90143, Palermo, Italy
Massimo Castellucci
Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), Ophthalmology Institute, University of Palermo, 90143, Palermo, Italy
Vincenza Maria Elena Bonfiglio
Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), Ophthalmology Institute, University of Palermo, 90143, Palermo, Italy
Sergio Zaccaria Scalinci
Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40121, Italy
Giorgia Abate
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy
Rosalia D'Angelo
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy
Antonina Sidoti
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, 98125, Italy
Aims: Maternally inherited diabetes and deafness (MIDD) is a complex disorder characterized by multiorgan clinical manifestations, including diabetes, hearing loss, and ophthalmic complications. This pilot study aimed to elucidate the intricate interplay between nuclear and mitochondrial genetics, epigenetic modifications, and their potential implications in the pathogenesis of MIDD. Main methods: A comprehensive genomic approach was employed to analyze a Sicilian family affected by clinically characterized MIDD, negative to the only known causative m.3243 A > G variant, integrating whole-exome sequencing and whole-genome bisulfite sequencing of both nuclear and mitochondrial analyses. Key findings: Rare and deleterious variants were identified across multiple nuclear genes involved in retinal homeostasis, mitochondrial function, and epigenetic regulation, while complementary mitochondrial DNA analysis revealed a rich tapestry of genetic diversity across genes encoding components of the electron transport chain and ATP synthesis machinery. Epigenetic analyses uncovered significant differentially methylated regions across the genome and within the mitochondrial genome, suggesting a nuanced landscape of epigenetic modulation. Significance: The integration of genetic and epigenetic data highlighted the potential crosstalk between nuclear and mitochondrial regulation, with specific mtDNA variants influencing methylation patterns and potentially impacting the expression and regulation of mitochondrial genes. This pilot study provides valuable insights into the complex molecular mechanisms underlying MIDD, emphasizing the interplay between nucleus and mitochondrion, tracing the way for future research into targeted therapeutic interventions and personalized approaches for disease management.
