Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America.
Department of Internal Medicine, National Taiwan University Medical College, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei, Taiwan; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.
Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):878-892. doi: 10.1016/j.bbabio.2018.07.002. Epub 2018 Jul 8.
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.
线粒体功能障碍与 2 型糖尿病（T2DM）和代谢综合征（MS）有关，已报道线粒体 DNA（mtDNA）tRNA 和重复突变以及 mtDNA 单倍群谱系。我们从台湾确定了 19 个台湾 T2DM 和 MS 家系，具有潜在的母系遗传，其中一个家系在 N9a3 单倍群背景下携带致病性 mtDNA tRNA 核苷酸（nt）3243A>G 突变。然后，我们招募了三个独立的台湾队列，两个来自台北（N=498，平均年龄 52，N=1002，平均年龄 44），一个来自非城市环境（N=501，平均年龄 57）。所有三个队列都评估了一系列代谢参数，确定了他们的 mtDNA 单倍群，并将单倍群与 T2DM/MS 表型相关联。逻辑回归分析显示，mtDNA 单倍群 D5、F4 和 N9a 赋予 T2DM 保护，而单倍群 F4 和 N9a 是高血压（HTN）的危险因素，F4 是肥胖（OB）的危险因素。此外，与 F4 相关的常见 5263C>T（ND2 A165V）变体与高血压（HTN）相关。用 mtDNA 单倍群 B4 和 F1 的宏单倍群 N（由变体 m.ND3 10398A（114T）和 m.ATP6 8701A（59T）定义）和宏单倍群 M（变体 m.ND3 10398G（114A）和 m.ATP6 8701G（59A）制备的细胞杂种（mtDNA 变体 m.ND3 10398G（114A）和 m.ATP6 8701G（59A）。此外，还制备了带有和不带有报道与 T2DM 相关的 mtDNA 变体 ND1 3394T>C（Y30H）的单倍群 B4 和 F1 细胞杂种。对这些细胞杂种中线粒体复合物 I 的测定表明，与 M 细胞杂种相比，宏单倍群 N 细胞杂种的活性较低，与 B4 细胞杂种相比，单倍群 F 细胞杂种的活性较低，并且 ND1 3394T>C（Y30H）变体降低了 B4 和 F1 背景上的复合物 I，但具有非常不同的累积效应。这些数据支持这样的假设，即功能性 mtDNA 变体可能有助于发展 T2DM 和 MS 的风险。
