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
复制标题
mtDNA 单倍群 N9a 通过改变线粒体功能和细胞内线粒体信号增加 2 型糖尿病的风险
DOI：
10.2337/db17-0974
复制
发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
Lyu, Jianxin
中科院分区：
文献类型：
--
作者：
Fang, Hezhi;Hu, Nianqi;Lyu, Jianxin
线粒体DNA（mtDNA）单倍型群与2型糖尿病（T2 D）的发病率相关;然而，其在T2 D中的潜在作用仍不清楚。在此，我们报告mtDNA单倍型群N9 a与中国南方2型糖尿病发病风险增加相关（比值比1.999 [95%CI 1.229-3.251]，P = 0.005）。通过使用transmitochondrial技术，我们证明了呼吸链复合物的活性在mtDNA单倍型群N9 a（N9 a1和N9 a10 a）的情况下低于三个非N9 a单倍型群（D4 j，G3 a2和Y1），这可能导致线粒体功能和线粒体氧化还原状态的改变。转录组分析显示，OXPHOS功能和代谢调控显着不同N9 a和非N9 a胞质杂种。此外，在N9 a胞质杂交体中，胰岛素刺激的葡萄糖摄取可能至少部分地通过增强ERK 1/2磷酸化和随后的TLR 4活化的刺激而被抑制，这被发现是由N9 a胞质杂交体中升高的氧化还原状态介导的。虽然目前还不清楚其他信号通路（例如，Wnt信号通路）与单倍型N9 a的T2 D易感性有关，我们的数据表明，在mtDNA单倍型N9 a的情况下，T2 D受到影响，至少部分是通过ERK 1/2过度刺激和随后的TLR 4激活。
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.