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  2. 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

  • Diabetes. 2018 Jul;67(7):1441-1453. doi: 10.2337/db17-0974.
Hezhi Fang 1 Nianqi Hu 2 Qiongya Zhao 2 Bingqian Wang 2 Huaibin Zhou 2 Qingzi Fu 2 Lijun Shen 2 Xiong Chen 3 Feixia Shen 3 Jianxin Lyu 1 4
Affiliations

Affiliations

  • 1 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China fangh@wmu.edu.cn ljx@wmu.edu.cn ljx@hmc.edu.cn.
  • 2 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
Abstract

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], P = 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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