Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

Yu CHEN; Liang GONG; Xingshu CHEN; Rui WANG; Yongjun LUO

doi:10.16016/j.1000-5404.201812008

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Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

更新时间：2026-03-02

- Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema
- Journal of Third Military Medical University Vol. 41, Issue 8, Pages: 734-740(2019)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)陆军卫勤训练基地军事医学地理学教研室，全军战救训练技术与器材研发实验室Development, Army Health Service Training Base, Army Medical University (Third Military Medical University), Chongqing, 400038, China
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81372125);the Key Special Program of Logistic Scientific Research of PLA(BLJ18J005)
- DOI：10.16016/j.1000-5404.201812008
  CLC： R339.54;R394.1;R541.63
- Received：03 December 2018，
  
  Published：30 April 2019
- 稿件说明：
移动端阅览
Yu CHEN, Liang GONG, Xingshu CHEN, et al. Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema[J]. Journal of Third Military Medical University, 2019, 41(8): 734-740.
DOI：

Yu CHEN, Liang GONG, Xingshu CHEN, et al. Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema[J]. Journal of Third Military Medical University, 2019, 41(8): 734-740. DOI： 10.16016/j.1000-5404.201812008.

摘要

目的

探讨线粒体DNA(mitochondrion DNA，mtDNA)3010A/G基因型变异导致高原肺水肿的可能机制。

方法

筛选线粒体DNA3010-5178-10400的单倍型组合A-C-C和G-C-C，以ρ

206细胞为供体，构建mt3010A基因型和mt3010G基因型融合细胞。经1%O

处理24 h后，采用流式细胞术检测两种融合细胞的活性氧(reactive oxygen species，ROS)、线粒体膜电位(mitochondrial membrane potential，MMP)，化学发光法检测三磷酸腺苷(adenosine triphosphate，ATP)含量，蛋白印迹法检测电压依赖性阴离子通道蛋白-1(voltage-dependent anion channel1，VDAC1)和Bax蛋白含量，荧光定量聚合酶链式法检测线粒体拷贝数、ERK、JNK、TFAM、ATP5A1和ATP5I基因的表达情况。

结果

经1%O

处理24 h后：mt3010G基因型融合细胞的ROS、MMP、ATP含量、线粒体拷贝数以及VDAC1、Bax蛋白表达与mt3010A基因型相似，差异无统计学意义(

0.05)。mt3010A融合细胞的ERK、JNK、TFAM、ATP5A1和ATP5I基因表达显著高于mt3010G融合细胞(

0.05)。

结论

mtDNA3010A/G变异能够影响线粒体的能量代谢，能量代谢异常可能参与了高原肺水肿的发病机制。

Abstract

Objective

To investigate the mechanism through which mtDNA3010 genotype variation leads to high-altitude pulmonary edema.

Methods

We assessed the functional impact of mtDNA3100 A/G genotype variation while maintaining C genotypes at the sites of mtDNA5178 and mtDNA10400. Two haplotype fusion cell models with genotype combinations at mtDNA3010

5178 and 10400 of A-C-C and G-C-C were established using mitochondrial DNA-depleted ρ

206 cells. The 2 fusion cell models were exposed to 1% O

for 24 h

and the production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) of the cells were detected with flow cytometry. The content of ATP was detected using a chemiluminescence method

and the expression levels of voltage-dependent anion channel1 (VDAC1) and Bax proteins were detected using Western blotting. Quantitative RT-PCR was employed to determine the mitochondrial copy number and the expression of ERK

JNK

TFAM

ATP5A1 and A

TP5I.

Results

In mt3010A and mt3010G fusion cells

the exposure to 1% O

for 24 h did not produce significant differences in the fluorescence intensity of ROS

MMP

ATP content

mitochondrial DNA copy number

or the relative protein expression levels of VDAC1 and Bax (all

0.05).The expression levels of ERK

JNK

TFAM

ATP5A1 and ATP5I genes were significantly higher in mtDNA3010A fusion cells than those in mtDNA3010G fusion cells after the hypoxic exposure (

0.05).

Conclusion

mtDNA3010A/G variation can affect energy metabolism of the mitochondria

and the disturbance in energy metabolism may contribute to the pathogenesis of high-altitude pulmonary edema.

关键词

Keywords

references

PENNARDT A. High-altitude pulmonary edema[J]. Curr Sports Med Rep, 2013, 12(2): 115-119. DOI: 10.1249/jsr.0b013e318287713b.

罗勇军, 高钰琪.高原肺水肿遗传易感性机制的研究进展[J].中华结核和呼吸杂志, 2011, 34(2): 135-137. DOI: 10.3760/cma.j.issn.1001-0939.2011.02.018.

LUO Y J, GAO Y Q. Progress in the study of gene polymorphisms and high altitude pulmonary edema susceptibility[J]. Chin J Tubercul Respir Dis, 2011, 34(2): 135-137. DOI: 10.3760/cma.j.issn.1001-0939.2011.02.018.

LUO Y J, ZOU Y L, GAO Y Q. Gene polymorphisms and high-altitude pulmonary edema susceptibility: A 2011 update[J]. Respiration, 2012, 84(2): 155-162. DOI: 10.1159/000336625.

LUO Y J, GAO W X, LI S Z, et al . Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese[J ] . Genet Mol Res, 2012, 11(4): 3658-3667. DOI: 10.4238/2012.october.9.1.

LI D, SUN Y P, ZHUANG Q Q, et al . Mitochondrial dysfunction caused by m.2336T > C mutation with hypertrophic cardiomyopathy in cybrid cell lines[J ] . Mitochondrion, 2018. DOI: 10.1016/j.mito.2018.08.005.

罗勇军, 刘福玉, 陈丽, 等.高原习服适应中白细胞线粒体DNA拷贝数的变化规律[J].第三军医大学学报, 2011, 33(4): 359, 375. DOI: 10.16016/j.1000-5404.2011.04.002.

LU O Y J, LIU F Y, CHEN L, et al . Changes in mitochondrial DNA copy number of leukocytes in high altitude adaptation[J ] . J Third Mil Med Univ, 2011, 33(4): 359, 375. DOI: 10.16016/j.1000-5404.2011.04.002.

罗勇军, 刘昕.实时荧光定量PCR标准品的制备及应用[J].重庆医学, 2005, 34(3): 414-415. DOI: 10.3969/j.issn.1671-8348.2005.03.045.

LUO Y J, LIU X. The method of preparation for the standard plasmids of real-time PCR and its application in the experiments[J]. Chongqing Med, 2005, 34(3): 414-415. DOI: 10.3969/j.issn.1671-8348.2005.03.045.

LIU Y Q, LI Y, ZHU C, et al . Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNAMet 4467 C > A mutation in a Han Chinese family with maternally inherited hypertension[J ] . Sci Rep, 2017, 7(1): 3034. DOI: 10.1038/s41598-017-03303-w.

SMEETS H J, SALLEVELT S C, DREESEN J C, et al . Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis[J ] . Ann N Y Acad Sci, 2015, 1350(1): 29-36. DOI: 10.1111/nyas.12866.

罗勇军, 高文祥, 刘福玉, 等.线粒体单倍群M中mtDNA 5351G和6680C基因型与高原肺水肿易感性的关联[J].中国呼吸与危重监护杂志, 2011, 10(1): 50-53. DOI: 10.3969/j.issn.1671-6205.2011.01.012.

LUO Y J, GAO W X, LIU F Y, et al . Associations between mt5351g and mt6680c genotypes in mtDNA haplogroup M and susceptibility to high altitude pulmonary edema among the Hans[J ] . Chin J Respir Crit Care Med, 2011, 10(1): 50-53. DOI: 10.3969/j.issn.1671-6205.2011.01.012.

LUO Y J, GAO W X, CHEN Y, et al . Rare mitochondrial DNA polymorphisms are associated with high altitude pulmonary edema (HAPE) susceptibility in Han Chinese[J ] . Wilderness Environ Med, 2012, 23(2): 128-132. DOI: 10.1016/j.wem.2012.02.003.

JIANG C H, CUI J H, LIU F Y, et al . Mitochondrial DNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a risk factor of high altitude polycythemia[J ] . PLoS ONE, 2014, 9(1): e87775. DOI: 10.1371/journal.pone.0087775.

GOYER I, ISEPPON M, THIBAULT C, et al . Lactic acidosis with chloramphenicol treatment in a child with cystic fibrosis[J ] . J Popul Ther Clin Pharmacol, 2017, 24(1): 40-45. DOI: 10.22374/1710-6222.24.1.5.

HUANG C Y, CHEN J Y, KUO C H, et al . Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1R upregulation are required for doxorubicin-induced cardio-toxicity[J ] . J Cell Physiol, 2018, 233(1): 463-475. DOI: 10.1002/jcp.25905.

BANOTH B, CASSEL S L. Mitochondria in innate immune signaling[J]. Transl Res, 2018, 202: 52-68. DOI: 10.1016/j.trsl.2018.07.014.

MURRAY A J, MONTGOMERY H E, FEELISCH M, et al . Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications[J ] . Biochem Soc Trans, 2018, 46(3): 599-607. DOI: 10.1042/bst20170502.

MURRAY A J. Energy metabolism and the high-altitude environment[J]. Exp Physiol, 2016, 101(1): 23-27. DOI: 10.1113/ep085317.

MURRAY A J, HORSCROFT J A. Mitochondrial function at extreme high altitude[J]. J Physiol(Lond), 2016, 594(5): 1137-1149. DOI: 10.1113/jp270079.

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