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

Ding, Yu; Shunrong, Zhang; Guo, Qinxian; Zheng, Hui

doi:10.2147/dmso.s363978

Cited by 8 publications

(6 citation statements)

References 84 publications

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Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Li,

Shang,

et al. 2024

PGPM

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Background Mutations in mitochondrial tRNA (mt-tRNA) could be the origin of some type 2 diabetes mellitus (T2DM) cases, but the mechanism remained largely unknown. Aim The aim of this study was to assess the impact of a novel mitochondrial tRNA Cys /tRNA Tyr A5826G mutation on the development and progression of T2DM. Methods 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. 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 tRNA Cys and tRNA Tyr , 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. Conclusion 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 tRNA Cys /tRNA Tyr , our study provided novel insight into the molecular pathogenesis, early diagnosis, prevention and clinical treatment for mitochondrial diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Li,

Shang,

et al. 2024

PGPM

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

et al. 2023

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Type 2 diabetes mellitus (T2DM) is a common endocrine disorder which remains a large challenge for clinicians. Previous studies have suggested that mitochondrial dysfunction plays an active role in T2DM progression, but a detailed mechanism is still elusive. In the current study, two Han Chinese families with maternally inherited T2DM were evaluated using clinical, genetic, molecular, and biochemical analyses. The mitochondrial genomes were PCR amplified and sequenced. Phylogenetic and bioinformatic analyses were used to assess the potential pathogenicity of mitochondrial DNA (mtDNA) mutations. Interestingly, the matrilineal relatives of these pedigrees exhibited variable severity of T2DM, in particular, the age at onset of T2DM varied from 26 to 65 years, with an average of 49 years. Sequence analysis revealed the presence of ND4 G11696A mutation, which resulted in the substitution of an isoleucine for valine at amino acid (AA) position 312. Indeed, this mutation was present in homoplasmy only in the maternal lineage, not in other members of these families, as well as 200 controls. Furthermore, the m.C5601T in the tRNAAla and novel m.T5813C in the tRNACys, showing high evolutional conservation, may contribute to the phenotypic expression of ND4 G11696A mutation. In addition, biochemical analysis revealed that cells with ND4 G11696A mutation exhibited higher levels of reactive oxygen species (ROS) productions than the controls. In contrast, the levels of mitochondrial membrane potential (MMP), ATP, mtDNA copy number (mtDNA-CN), Complex I activity, and NAD+/NADH ratio significantly decreased in cell lines carrying the m.G11696A and tRNA mutations, suggesting that these mutations affected the respiratory chain function and led to mitochondrial dysfunction that was involved in T2DM. Thus, our study broadened the clinical phenotypes of m.G11696A mutation.

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“…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.…”

Section: Association Between Transfer Rna Mutations and Type 2 Diabet...mentioning

confidence: 99%

Transfer RNA Mutation Associated with Type 2 Diabetes Mellitus

Rahmadanthi,

Maksum

2023

Biology

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Transfer RNA (tRNA) genes in the mitochondrial DNA genome play an important role in protein synthesis. The 22 tRNA genes carry the amino acid that corresponds to that codon but changes in the genetic code often occur such as gene mutations that impact the formation of adenosine triphosphate (ATP). Insulin secretion does not occur because the mitochondria cannot work optimally. tRNA mutation may also be caused by insulin resistance. In addition, the loss of tRNA modification can cause pancreatic β cell dysfunction. Therefore, both can be indirectly associated with diabetes mellitus because diabetes mellitus, especially type 2, is caused by insulin resistance and the body cannot produce insulin. In this review, we will discuss tRNA in detail, several diseases related to tRNA mutations, how tRNA mutations can lead to type 2 diabetes mellitus, and one example of a point mutation that occurs in tRNA.

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

Cited by 8 publications

References 84 publications

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

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

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

Transfer RNA Mutation Associated with Type 2 Diabetes Mellitus

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