Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications

Niu, Qing; Zhang, Wanlin; Wang, Hailin; Guan, Xiaomin; Lü, Jianxin; Li, Wei

doi:10.3892/etm.2015.2751

Cited by 12 publications

(16 citation statements)

References 31 publications

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“…The participants without diabetes were people in whom the fasting plasma glucose concentration was ,6.1 mmol/L and blood glycosylated hemoglobin (HbA 1c ) level was ,6.2% (44 mmol/mol). We have described 675 patients and 649 control subjects used here in a previous study (27). Informed consent was obtained from all participants under protocols approved by the ethics committee of Wenzhou Medical University.…”

Section: Study Participantsmentioning

confidence: 99%

“…Complete mtDNA sequence was Sanger sequenced for 347 T2D patients and 383 control subjects by using 24 previously reported pairs of mtDNA primers (28). The mtDNA of 235 T2D patients and 141 control subjects was completely sequenced previously (27); for all other study participants, Sanger sequencing was performed using two pairs of mtDNA primers (Supplementary Table 1). SNPs of each participant were identified by comparing the obtained sequences with the revised Cambridge Reference Sequence by using CodonCode Aligner 3.0.1 (CodonCode Corporation, Centerville, VA).…”

Section: Mtdna Sequencing and Genotypingmentioning

confidence: 99%

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mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals

Fang

Zhao

et al. 2018

Diabetes

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Mitochondrial DNA (mtDNA) haplogroups have been associated with the incidence of type 2 diabetes (T2D); however, their underlying role in T2D remains poorly elucidated. Here, we report that mtDNA haplogroup N9a was associated with an increased risk of T2D occurrence in Southern China (odds ratio 1.999 [95% CI 1.229-3.251], = 0.005). By using transmitochondrial technology, we demonstrated that the activity of respiratory chain complexes was lower in the case of mtDNA haplogroup N9a (N9a1 and N9a10a) than in three non-N9a haplogroups (D4j, G3a2, and Y1) and that this could lead to alterations in mitochondrial function and mitochondrial redox status. Transcriptome analysis revealed that OXPHOS function and metabolic regulation differed markedly between N9a and non-N9a cybrids. Furthermore, in N9a cybrids, insulin-stimulated glucose uptake might be inhibited at least partially through enhanced stimulation of ERK1/2 phosphorylation and subsequent TLR4 activation, which was found to be mediated by the elevated redox status in N9a cybrids. Although it remains unclear whether other signaling pathways (e.g., Wnt pathway) contribute to the T2D susceptibility of haplogroup N9a, our data indicate that in the case of mtDNA haplogroup N9a, T2D is affected, at least partially through ERK1/2 overstimulation and subsequent TLR4 activation.

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Section: Study Participantsmentioning

confidence: 99%

Section: Mtdna Sequencing and Genotypingmentioning

confidence: 99%

mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals

Fang

Zhao

et al. 2018

Diabetes

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“…Also in the Japanese, M8a was found to be at increased risk of T2DM and B4c with predisposition to OB [25]. By contrast, in the Chinese haplogroup N9a has been found to be at increased risk of T2DM [26] and diabetic retinopathy [27]. Among Han Chinese M9 was found to be at increased risk of T2DM [28] as was M8a [27].…”

Section: Genetic Analysis Of East Asian Mtdna Variants With T2dm and Msmentioning

confidence: 99%

“…By contrast, in the Chinese haplogroup N9a has been found to be at increased risk of T2DM [26] and diabetic retinopathy [27]. Among Han Chinese M9 was found to be at increased risk of T2DM [28] as was M8a [27]. In a Taiwanese sample, haplogroups B4a1a and E2b1 were found to be significantly associated with T2DM, while haplogroup D4 was protective [29].…”

Section: Genetic Analysis Of East Asian Mtdna Variants With T2dm and Msmentioning

confidence: 99%

Mitochondrial DNA associations with East Asian metabolic syndrome

Chalkia

Chang

Derbeneva

et al. 2018

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Mitochondrial dysfunction has repeatedly been reported associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), as have mitochondrial DNA (mtDNA) tRNA and duplication mutations and mtDNA haplogroup lineages. We identified 19 Taiwanese T2DM and MS pedigrees from Taiwan, with putative matrilineal transmission, one of which harbored the pathogenic mtDNA tRNA nucleotide (nt) 3243A>G mutation on the N9a3 haplogroup background. We then recruited three independent Taiwanese cohorts, two from Taipei (N = 498, mean age 52 and N = 1002, mean age 44) and one from a non-urban environment (N = 501, mean age 57). All three cohorts were assessed for an array of metabolic parameters, their mtDNA haplogroups determined, and the haplogroups correlated with T2DM/MS phenotypes. Logistic regression analysis revealed that mtDNA haplogroups D5, F4, and N9a conferred T2DM protection, while haplogroups F4 and N9a were risk factors for hypertension (HTN), and F4 was a risk factor for obesity (OB). Additionally, the 5263C>T (ND2 A165V) variant commonly associated with F4 was associated with hypertension (HTN). Cybrids were prepared with macro-haplogroup N (defined by variants m.ND3 10398A (114T) and m.ATP6 8701A (59T)) haplogroups B4 and F1 mtDNAs and from macro-haplogroup M (variants m.ND3 10398G (114A) and m.ATP6 8701G (59A)) haplogroup M9 mtDNAs. Additionally, haplogroup B4 and F1 cybrids were prepared with and without the mtDNA variant in ND1 3394T>C (Y30H) reported to be associated with T2DM. Assay of mitochondria complex I in these cybrids revealed that macro-haplogroup N cybrids had lower activity than M cybrids, that haplogroup F cybrids had lower activity than B4 cybrids, and that the ND1 3394T>C (Y30H) variant reduced complex I on both the B4 and F1 background but with very different cumulative effects. These data support the hypothesis that functional mtDNA variants may contribute to the risk of developing T2DM and MS.

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“…mtDNA haplogroups and their characteristic SNPs—for example, m.10398A/G [2], m.5178C/A [3], and m.152T/C [4]—can be advantageous or detrimental and have been implicated in a number of diseases and pathological conditions, including cancer [5], aging [6], diabetes [7], osteoarthritis [8], schizophrenia [9], and Leber's hereditary optic neuropathy [10]. A phylogenetic tree of L3 subhaplogroups that migrated from Africa to East Asia [11, 12] revealed that many of the subclades were associated with metabolic and degenerative diseases [13, 14]. The link between mtDNA haplogroup/SNPs and disease has been attributed to possible changes in mitochondrial reactive oxygen species (ROS) levels, respiration capacity, and ATP production [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Generation and Bioenergetic Profiles of Cybrids with East Asian mtDNA Haplogroups

Zhou

Nie

Qiu

et al. 2017

Oxidative Medicine and Cellular Longevity

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Human mitochondrial DNA (mtDNA) variants and haplogroups may contribute to susceptibility to various diseases and pathological conditions, but the underlying mechanisms are not well understood. To address this issue, we established a cytoplasmic hybrid (cybrid) system to investigate the role of mtDNA haplogroups in human disease; specifically, we examined the effects of East Asian mtDNA genetic backgrounds on oxidative phosphorylation (OxPhos). We found that mtDNA single nucleotide polymorphisms such as m.489T>C, m.10398A>G, m.10400C>T, m.C16223T, and m.T16362C affected mitochondrial function at the level of mtDNA, mtRNA, or the OxPhos complex. Macrohaplogroup M exhibited higher respiratory activity than haplogroup N owing to its higher mtDNA content, mtRNA transcript levels, and complex III abundance. Additionally, haplogroup M had higher reactive oxygen species levels and NAD+/NADH ratios than haplogroup N, suggesting difference in mitonuclear interactions. Notably, subhaplogroups G2, B4, and F1 appeared to contribute significantly to the differences between haplogroups M and N. Thus, our cybrid-based system can provide insight into the mechanistic basis for the role of mtDNA haplogroups in human diseases and the effect of mtDNA variants on mitochondrial OxPhos function. In addition, studies of mitonuclear interaction using this system can reveal predisposition to certain diseases conferred by variations in mtDNA.

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Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications

Cited by 12 publications

References 31 publications

mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals

mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals

Mitochondrial DNA associations with East Asian metabolic syndrome

Generation and Bioenergetic Profiles of Cybrids with East Asian mtDNA Haplogroups

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