Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations

Abstract

Background Mutations in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). In particular, m.A3243G is the most common T2DM-related mtDNA mutation in many families worldwide. However, the clinical features and pathophysiology of m.A3243G-induced T2DM are largely undefined. Methods Two pedigrees with maternally inherited T2DM were underwent clinical, molecular and biochemical assessments. The mtDNA genes were PCR amplified and sequenced. Mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) were measured in polymononuclear leukocytes derived from three patients with both the m.A3243G and m.T14502C mutations, three patients with only the m.A3243G mutation and three controls without these mutations. Moreover, GJB2, GJB3 and GJB6 mutations were screened by PCR-Sanger sequencing. Results Members of the two pedigrees manifestated variable clinical phenotypes including diabetes and hearing and vision impairments. The age at onset of T2DM varied from 31 to 66 years, with an average of 41 years. Mutational analysis of mitochondrial genomes indicated the presence of the m.A3243G mutation in both pedigrees. Matrilineal relatives in one of the pedigrees harbored the coexisting of m.A3243G and m.T14502C mutations. Remarkably, the m.T14502C mutation, which causes the substitution of a conserved isoleucine for valine at position 58 in ND6 mRNA, may affect the mitochondrial respiratory chain functions. Biochemical analysis revealed that cell lines bearing both the m.A3243G and m.T14502C mutations exhibited greater reductions in ATP levels and increased ROS production compared with those carrying only the m.A3243G mutation. However, we did not find any mutations in the GJB2, GJB3 and GJB6 genes. Conclusion Our study indicated that mitochondrial diabetes is associated with the tRNA Leu(UUR) A3243G and ND6 T14502C mutations.

Identification of a Novel Mitochondrial tRNA Mutation in Chinese Family with Type 2 Diabetes Mellitus

“…In fact, the homoplasmic m.C14668T mutation caused the well-conserved Tyr to Asn, was first described to be associated with schizophrenia, bipolar disorder and major depressive disorder, 39 and the conserved Tyr to Asn transition perturbed the structural and function of ND6 , thereby affecting Complex I deficiency, as in the case of T2DM associated ND6 T14502C mutation. 11 …”

“…In fact, the homoplasmic m.C14668T mutation caused the well-conserved Tyr to Asn, was first described to be associated with schizophrenia, bipolar disorder and major depressive disorder, 39 and the conserved Tyr to Asn transition perturbed the structural and function of ND6, thereby affecting Complex I deficiency, as in the case of T2DM associated ND6 T14502C mutation. 11 Trans-mitochondrial cybrids were created by fusing cells devoid of mtDNA (ρ 0 cells) with cytoplasts from different individuals, so the resultant cybrids had uniform nuclear background but different mtDNA. 50 With the development and use of the cybrid model, questions related to the importance of the mtDNA variants and mitochondrial-nuclear interactions can be addressed.…”

“…[5][6][7][8] In particular, the well-known m.A3243G mutation in tRNA Leu(UUR) was implicated in the pathogenesis and progression of T2DM in many families worldwide. [9][10][11] This mutation affected the structural stability, aminoacylation rate and post-transcriptional modification of tRNA Leu(UUR) . 12 In addition to the m.A3243G mutation, some case-control studies suggested that tRNA Trp A5514G and tRNA Ser(AGY) C12337T, 13 tRNA Glu A14692G, 14 tRNA Ala T5587C and ND5 T12338C 15 mutations were associated with T2DM.…”

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

“…The cell lines with m.G11696A showed significant reductions in Complex I activity, as in the case of T2DM-associated ND6 T14502C mutation [ 63 ]. Complex I was a large protein complex responsible for acquiring electrons by oxidizing NADH to NAD + and transferring these electrons to CoQ [ 64 ].…”

Transfer RNA Mutation Associated with Type 2 Diabetes Mellitus

“…Research has established a relationship between these mutations and ATP levels. A study was conducted on three subjects with both A3243G and T14502C mutations, three subjects with only the A3243G primary mutation, and three healthy individuals, demonstrating that ATP levels were further decreased in the presence of secondary mutations [ 129 ]. This can occur due to the interference of mutations with ATP formation, as previously described.…”