Mitochondrial DNA 10609T Promotes Hypoxia-Induced Increase of Intracellular ROS and Is a Risk Factor of High Altitude Polycythemia

Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson’s chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95%CI: 1.020–2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95%CI: 1.250–5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor.

低压缺氧（Hypobaric hypoxia）是高原红细胞增多症（high altitude polycythemia, HAPC）的主要致病因素。线粒体是一类关键细胞器，可消耗高浓度氧气并合成三磷酸腺苷（ATP）。我们提出如下假说：线粒体可能在高原红细胞增多症的发病过程中处于核心地位，而线粒体DNA（mitochondrial DNA, mtDNA）单核苷酸多态性（single nucleotide polymorphism, SNPs）或参与其发生发展。首先，我们针对迁入青藏高原的汉族人群开展了一项病例对照研究，以探究mtDNA变异与高原红细胞增多症之间的关联。皮尔逊卡方检验结果显示，高原红细胞增多症组中mtDNA 8414T（MU）的等位基因频率为19.5%，显著高于对照组的13.0%（P=0.04，比值比OR=1.615，95%置信区间CI：1.020~2.555）。在校正环境因素后进行的多因素logistic回归分析显示，mtDNA 10609T（WT）与高原红细胞增多症的发病风险升高呈显著相关（P<0.01，OR=2.558，95%置信区间CI：1.250~5.236）。其次，为验证上述关联，我们构建了线粒体杂交细胞（transmitochondrial cybrids）并开展了体外实验，结果显示mtDNA 10609变异可促进缺氧诱导的细胞内活性氧（reactive oxygen species, ROS）水平升高，而mtDNA 8414变异则无此效应。本研究结果证实，在汉族人群中，mtDNA 10609T可促进缺氧诱导的细胞内活性氧水平升高，是高原红细胞增多症的风险因子。