Maternally transmitted diabetes mellitus may be associated with mitochondrial ND5 T12338C and tRNAAla T5587C variants

Jiang, Zhaochang; Cai, Xiaobo; Kong, Jing; Zhang, Ruyi; Ding, Yu

doi:10.1007/s11845-021-02911-w

Cited by 3 publications

(2 citation statements)

References 35 publications

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“… 52 At the molecular level, m.T12338C altered well-conserved methionine with threonine; therefore, the ND5 mRNA was expected to be shortened by two AAs. 53 Using cybrid cell models, the m.T12338C mutation decreased the stability of the ND5 polypeptide, affecting the assembly and activity of respiratory chain complexes. 54 Therefore, m.T12338C causes a mitochondrial dysfunction that plays a key role in PCOS-IR.…”

Section: Pcos-ir–associated Mtdna Mutationsmentioning

confidence: 99%

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

Dong

Liu

Zhuo

et al. 2023

DMSO

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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.

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Section: Pcos-ir–associated Mtdna Mutationsmentioning

confidence: 99%

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

Dong

Liu

Zhuo

et al. 2023

DMSO

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“…[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. In fact, mt-tRNA pathogenic mutations have structural and functional consequences, such as affecting the tRNA structure, altering 5' or 3' processing of tRNAs, CCA addition and leading to defects in chemical modifications.…”

Section: Introductionmentioning

confidence: 99%

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

Li,

Shang,

et al. 2024

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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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Functional analysis of the novel mitochondrial tRNA^Trp and tRNA^Ser(AGY) variants associated with type 2 diabetes mellitus

Ding,

Yu,

Guo

et al. 2024

World J Diabetes

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BACKGROUND 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. AIM To assess the potential pathogenicity of T2DM-associated m.A5514G and m.C12237T variants at genetic, molecular, and biochemical levels. METHODS 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. RESULTS 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). CONCLUSION 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.

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Maternally transmitted diabetes mellitus may be associated with mitochondrial ND5 T12338C and tRNAAla T5587C variants

Cited by 3 publications

References 35 publications

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

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

Functional analysis of the novel mitochondrial tRNA^Trp and tRNA^Ser(AGY) variants associated with type 2 diabetes mellitus

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Maternally transmitted diabetes mellitus may be associated with mitochondrial ND5 T12338C and tRNAAla T5587C variants

Cited by 3 publications

References 35 publications

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

Potential Roles of mtDNA Mutations in PCOS-IR: A Review

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

Functional analysis of the novel mitochondrial tRNATrp and tRNASer(AGY) variants associated with type 2 diabetes mellitus

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Functional analysis of the novel mitochondrial tRNA^Trp and tRNA^Ser(AGY) variants associated with type 2 diabetes mellitus