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.

Mutations in mitochondrial tRNA (mt-tRNA) genes that result in mitochondrial dysfunction play important roles in type 2 diabetes mellitus (T2DM). We pre-viously reported a large Chinese pedigree with maternally inherited T2DM that harbors novel mt-tRNA Trp A5514G and tRNA Ser(AGY) C12237T variants, however, the effects of these mt-tRNA variants on T2DM progression are largely unknown.

To assess the potential pathogenicity of T2DM-associated m.A5514G and m.C12237T variants at genetic, molecular, and biochemical levels.

Cytoplasmic hybrid (cybrid) cells carrying both m.A5514G and m.C12237T variants, and healthy control cells without these mitochondrial DNA (mtDNA) variants were generated using trans-mitochondrial technology. Mitochondrial features, including mt-tRNA steady-state level, levels of adenosine triphosphate (ATP), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mtDNA copy number, nicotinamide adenine dinucleotide (NAD+)/NADH ratio, enzymatic activities of respiratory chain complexes (RCCs), 8-hydroxy-deo-xyguanine (8-OhdG), malondialdehyde (MDA), and superoxide dismutase (SOD) were examined in cell lines with and without these mt-tRNA variants.

Compared with control cells, the m.A5514G variant caused an approximately 35% reduction in the steady-state level of mt-tRNA Trp (P < 0.0001); however, the m.C12237T variant did not affect the mt-tRNA Ser(AGY) steady-state level (P = 0.5849). Biochemical analysis revealed that cells with both m.A5514G and m.C12237T variants exhibited more severe mitochondrial dysfunctions and elevated oxidative stress than control cells: ATP, MMP, NAD+/NADH ratio, enzyme activities of RCCs and SOD levels were markedly decreased in mutant cells (P < 0.05 for all measures). By contrast, the levels of ROS, 8-OhdG and MDA were significantly increased (P < 0.05 for all measures), but mtDNA copy number was not affected by m.A5514G and m.C12237T variants (P = 0.5942).

The m.A5514G variant impaired mt-tRNA Trp metabolism, which subsequently caused mitochondrial dysfunction. The m.C12237T variant did not alter the steady-state level of mt-tRNA Ser(AGY), indicating that it may be a modifier of the m.A5514G variant. The m.A5514G variant may exacerbate the pathogenesis and progression of T2DM in this Chinese pedigree.

Mutations in mitochondrial tRNA (mt-tRNA) could be the origin of some type 2 diabetes mellitus (T2DM) cases, but the mechanism remained largely unknown.

The aim of this study was to assess the impact of a novel mitochondrial tRNACys/tRNATyr A5826G mutation on the development and progression of T2DM.

A four-generation Han Chinese family with maternally inherited diabetes underwent clinical, genetic and biochemical analyses. The mitochondrial DNA (mtDNA) mutations of three matrilineal relatives were screened by PCR-Sanger sequencing. Furthermore, to see whether m.A5826G mutations affected mitochondrial functions, the cybrid cell lines were derived from three subjects with m.A5826G mutation and three controls without this mutation. ATP was evaluated by luminescent cell viability assay, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were determined by flow cytometry. The student's two-tailed, unpaired t-test was used to assess the statistical significance between the control and mutant results.

The age at onset of diabetes in this pedigree varied from 40 to 63 years, with an average of 54 years. Mutational analysis of mitochondrial genomes revealed the presence of a novel m.A5826G mutation. Interestingly, the m.A5826G mutation occurred at the conjunction between tRNACys and tRNATyr, a very conserved position that was critical for tRNAs processing and functions. Using trans-mitochondrial cybrid cells, we found that mutant cells carrying the m.A5826G showed approximately 36.5% and 22.4% reductions in ATP and MMP, respectively. By contrast, mitochondrial ROS levels increased approximately 33.3%, as compared with the wild type cells.

A novel m.A5826G mutation was identified in a pedigree with T2DM, and this mutation would lead to mitochondrial dysfunction. Thus, the genetic spectrum of mitochondrial diabetes was expanded by including m.A5826G mutation in tRNACys/tRNATyr, our study provided novel insight into the molecular pathogenesis, early diagnosis, prevention and clinical treatment for mitochondrial diabetes.

Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disease that affecting females in reproductive age. Insulin resistance (IR), an important molecular basis for PCOS, accounts for at least 75% of women carrying this syndrome. Although there have been many studies on PCOS-IR, the detailed mechanisms are not fully understood. As essential hub for energy generation, mitochondria are critical to insulin secretion and normal function, whereas mutations in mitochondrial DNA (mtDNA) result in mitochondrial dysfunctions contributing to the pathophysiology of PCOS-IR via the regulation of balance of oxidative stress (OS), energy deficiency, or hormone metabolism. In the current review, we summarize the clinical and molecular features of PCOS-IR and discuss molecular mechanisms related to mtDNA mutations.