Mitochondrial DNA variants in the pathogenesis and metabolic alterations of diabetes mellitus

Mitochondrial DNA (mtDNA) variants considerably affect diabetes mellitus by disturbing mitochondrial function, energy metabolism, oxidative stress response, and even insulin secretion. The m.3243 A > G variants is associated with maternally inherited diabetes and deafness (MIDD), where early onset diabetes and hearing loss are prominent features. Other types of mtDNA variants involve genes ND4 and tRNA Ala genes that increase susceptibility to type 2 diabetes. Understanding these variants will provide a basis for developing targeted therapy to improve mitochondrial function and metabolic health. This article reviews the impact of mtDNA variants in diabetes, specifically with regards to the m.3243 A > G variant effects on mitochondrial function and insulin secretion and other mtDNA variants that contribute to diabetes susceptibility, particularly ND4 and tRNA Ala gene variants. Data from extant literature were synthesised to obtain an understanding of how mtDNA variants affect diabetes pathogenesis. The main defect for MIDD is the m.3243 A > G variant, which comprises enhanced susceptibility to metabolic syndrome and type 2 diabetes, followed by mitochondrial dysfunction, insulin resistance, and beta-cell dysfunction. Other mtDNA variants have also been reported to enhance diabetes susceptibility through mitochondrial dysfunction and insulin resistance. Increased production of reactive oxygen species (ROS) resulting from mitochondrial malfunction adds to metabolic and tissue damage. This happens in tissues crucial to glucose homeostasis, and it represents an important contribution of mitochondrial dysfunction to metabolic disturbances in diabetes. These mechanisms would underlie the rationale for developing targeted therapies to preserve mitochondrial function and, hence improve the metabolic health of diabetic patients.