活化Drp1介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究

段晨阳; 向鑫明; 匡磊; 刘良明; 李涛

doi:10.16016/j.1000-5404.201907139

您当前的位置：

首页 >

文章列表页 >

活化Drp1介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究

基础医学 | 更新时间：2026-01-09

- 活化Drp1介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究
- Role of activated dynamin-related protein 1-mediated glutathione metabolism in regulation of mitochondrial dysfunction after hemorrhagic shock
- 第三军医大学学报 2020年42卷第1期页码：50-58
- 作者机构：
  
  400042 重庆, 陆军军医大学(第三军医大学)野战外科研究所战伤休克与输血研究室，创伤、烧伤与复合伤国家重点实验室
- 作者简介：
  
  [李涛，E-mail:lt200132@163.com LI Tao, E-mail:lt200132@163.com
- 基金信息：
  
  国家自然科学基金重点项目(81730059);国家自然科学基金青年科学基金(81700429)
- DOI：10.16016/j.1000-5404.201907139
  中图分类号： Q244;R363.22;R605.971
- 收稿：2019-07-08，
  
  修回：2019-09-08，
  
  纸质出版：2020-01-15
- 稿件说明：
移动端阅览
段晨阳, 向鑫明, 匡磊, 等. 活化Drp1介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究[J]. 第三军医大学学报, 2020,42(1):50-58.

Chenyang DUAN, Xinming XIANG, Lei KUANG, et al. Role of activated dynamin-related protein 1-mediated glutathione metabolism in regulation of mitochondrial dysfunction after hemorrhagic shock[J]. Journal of Third Military Medical University, 2020, 42(1): 50-58.
段晨阳, 向鑫明, 匡磊, 等. 活化Drp1介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究[J]. 第三军医大学学报, 2020,42(1):50-58. DOI： 10.16016/j.1000-5404.201907139.

Chenyang DUAN, Xinming XIANG, Lei KUANG, et al. Role of activated dynamin-related protein 1-mediated glutathione metabolism in regulation of mitochondrial dysfunction after hemorrhagic shock[J]. Journal of Third Military Medical University, 2020, 42(1): 50-58. DOI： 10.16016/j.1000-5404.201907139.

摘要

目的

探究失血性休克后活化Drp1介导线粒体功能改变与能量代谢之间的关系及其作用机制。

方法

60只C57雌鼠(8周龄，体质量约20 g)分为休克WT组与常态WT组(

=30)。60只Drp1 KO雌鼠(C57品系，8周龄，体质量约20 g)分为休克Drp1 KO组(作缺血休克处理)与常态Drp1 KO组(

=30)。观察失血性休克后血管组织能量代谢、线粒体代谢、线粒体功能、Drp1活性变化，以及干预Drp1对休克后能量代谢、线粒体代谢及其差异代谢物的影响。对血管平滑肌细胞进行Drp1过表达、外源性谷胱甘肽(10 mmol/L)处理后观察干预Drp1及谷胱甘肽对缺氧后ROS、线粒体膜电位等线粒体功能变化。

结果

休克后血管组织能量代谢减低、谷胱甘肽等线粒体代谢异常、线粒体ROS产生增高2.3倍、线粒体ATP含量减少67.8%、线粒体呼吸强度OCR减弱50%(

0.05)，缺氧后ROS水平增高4倍、线粒体膜电位减少76.7%(

0.05)，并且休克和缺氧后均发现Drp1发生活化及线粒体转位(

0.05)。常态WT组血管组织谷胱甘肽水平为(1.35±0.42)nmol/μg，休克WT组谷胱甘肽水平为(0.55±0.20)nmol/μg，休克Drp1 KO组血管组织谷胱甘肽水平(0.94±0.30)nmol/μg明显高于休克WT组(

0.05)。Drp1过表达后血管平滑肌细胞ROS水平增加3.3倍、线粒体膜电位减少70%(

0.05)，进一步外源性补充谷胱甘肽后ROS水平和线粒体膜电位明显改善(

0.05)。

结论

失血性休克后活化Drp1可通过抑制谷胱甘肽线粒体代谢引起线粒体功能障碍和机体能量代谢紊乱。

Abstract

Objective

To explore the relationship between activated dynamin-related protein 1 (Drp1)-mediated mitochondrial function and energy metabolism after hemorrhagic shock and clarify its potential mechanisms.

Methods

Sixty C57 female mice (8-weeks old

weighing about 20 g) were randomly divided into shock+WT group (

=30

treated with hemorrhagic shock) and Normal+WT group (

=30). Thirty Drp1 KO C57 female mice (8-weeks old

weighing about 20 g) were treated with hemorrhagic shock as shock+Drp1 KO group

and the other 30 KO mice were regarded as Normal+Drp1 KO group. The changes of energy metabolism

mitochondrial metabolism

mitochondrial functions as well as Drp1 activity in vascular tissues after hemorrhagic shock were observed in WT and KO mice respectively. Vascular smooth muscle cells (VSMCs) were treated with Drp1 over-expression and exogenous glutathione (10 mmol/L) to confirm the effects of Drp1 and glutathione on mitochondrial functions after shock.

Results

After hemorrhagic shock

the energy metabolism and mitochondrial metabolism

such as glutathione

were decreased significantly (

0.05)

mitochondrial reactive oxygen species (ROS) production were increased by 2.3 times (

0.05)

ATP content was decreased by 67.8% (

0.05)

and mitochondrial respiratory rates were decreased by 50% (

0.05). However

hypoxia resulted in the ROS production of VSMCs enhanced by 4 times and the mitochondrial membrane potential (ΔΨm) decreased by 76.7% (

0.05). What's more

both Drp1 activation and mitochondrial translocation were observed in shock-treated mice and hypoxia-induced VSMCs. The level of glutathione was 1.35±0.0.42 nmol/μg in normal+WT group

0.55±0.20 nmol/μg in shock+WT group

while the level in

shock+Drp1 KO group (0.94±0.30 nmol/μg) was much higher than that in shock+WT group (

0.05). Drp1 over-expression induced ROS level in VSMCs increased by 3.3 times and ΔΨm decreased by 70% (

0.05). After further exogenous glutathione supplementation

both ROS level and ΔΨm were improved significantly (

0.05).

Conclusion

Activated Drp1 after hemorrhagic shock induces mitochondrial dysfunctions and abnormal energy metabolism by inhibiting glutathione metabolism.

关键词

Keywords

references

DUAN C Y, ZHANG J, WU H L, et al . Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock[J ] . Mil Med Res, 2017, 4: 11. DOI:10.1186/s40779-017-0117-6 .

DUAN C Y, YANG G M, LI T, et al . Advances in vascular hyporeactivity after shock: the mechanisms and managements[J ] . Shock, 2015, 44(6): 524-534. DOI:10.1097/SHK. 0000000000000457.

LI Z Q, LI J, ZHANG S W, et al . Metabolomics analysis of gut barrier dysfunction in a trauma-hemorrhagic shock rat model[J ] . Biosci Rep, 2019, 39(1): BSR20181215. DOI:10.1042/ BSR20181215.

DUAN C Y, LI T, LIU L M. Efficacy of limited fluid resuscitation in patients with hemorrhagic shock: a meta-analysis[J]. Int J Clin Exp Med, 2015, 8(7): 11645-11656.

FONSECA T B, SÁNCHEZ-GUERRERO Á, MILOSEVIC I, et al . Mitochondrial fission requires DRP1 but not dynamins[J ] . Nature, 2019, 570(7761): E34-E42. DOI:10.1038/s41586- 019-1296-y.

DUAN C Y, CHEN K, YANG G M, et al . HIF-1α regulates Cx40-dependent vasodilatation following hemorrhagic shock in rats[J ] . Am J Transl Res, 2017, 9(3): 1277-1286.

DUAN C Y, CAO Z Z, TANG F Q, et al . MiRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis[J ] . Aging (Albany NY), 2019, 11(2): 448-466. DOI:10.18632/aging.101751.

TANG X Q, CHEN X F, CHEN H Z, et al . Mitochondrial sirtuins in cardiometabolic diseases[J ] . Clin Sci, 2017, 131(16): 2063-2078. DOI:10.1042/CS20160685.

SHIN H W, SHINOTSUKA C, TORⅡ S, et al . Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p[J ] . J Biochem, 1997, 122(3): 525-530. DOI:10.1093/oxfordjournals. jbchem.a021784.

ADACHI Y, ⅡJIMA M, SESAKI H. An unstructured loop that is critical for interactions of the stalk domain of Drp1 with saturated phosphatidic acid[J]. Small GTPases, 2018, 9(6): 472-479. DOI:10.1080/21541248.2017.1321614.

NISHIMURA A, SHIMAUCHI T, TANAKA T, et al . Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence[J ] . Sci Signal, 2018, 11(556): eaat5185. DOI:10.1126/scisignal. aat5185.

BARDAI F H, ORDONEZ D G, BAILEY R M, et al . Lrrk promotes tau neurotoxicity through dysregulation of actin and mitochondrial dynamics[J ] . PLoS Biol, 2018, 16(12): e2006265. DOI:10.1371/journal.pbio.2006265.

REHMAN J, ZHANG H J, TOTH P T, et al . Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer[J ] . FASEB J, 2012, 26(5): 2175-2186. DOI:10.1096/fj.11- 196543.

ZHAO J, ZHANG J, YU M, et al . Mitochondrial dynamics regulates migration and invasion of breast cancer cells[J ] . Oncogene, 2013, 32(40): 4814-4824. DOI:10.1038/onc.2012.494.

HAGENBUCHNER J, KUZNETSOV A V, OBEXER P, et al . BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery[J ] . Oncogene, 2013, 32(40): 4748-4757. DOI:10. 1038/onc.2012.500.

SONG Y, LI T, LIU Z G, et al . Inhibition of Drp1 after traumatic brain injury provides brain protection and improves behavioral performance in rats[J ] . Chem Biol Interact, 2019, 304: 173-185. DOI:10.1016/j.cbi.2019.03.013.

ZHANG L X, MA C, WANG X Y, et al . L ipopolysaccharide-induced proliferation and glycolysis in airway smooth muscle cells via activation of Drp1[J ] . J Cell Physiol, 2019, 234(6): 9255-9263. DOI:10.1002/jcp.27605.

SEIDKHANI-NAHAL A, ALLAMEH A, SOLEIMANI M. Antioxidant and reactive oxygen species scavenging properties of cellular albumin in HepG2 cells is mediated by the glutathione redox system[J]. Biotechnol Appl Biochem, 2019, 66(2): 163-171. DOI:10.1002/bab.1708.

SIMEUNOVIC D, ODANOVIC N, PLJESA-ERCEGOVAC M, et al . Glutathione transferase P1 polymorphism might be a risk determinant in heart failure[J ] . Dis Markers, 2019, 2019: 6984845. DOI:10.1155/2019/6984845.

KIM K Y, HWANG S K, PARK S Y, et al . L-Serine protects mouse hippocampal neuronal HT22 cells against oxidative stress-mediated mitochondrial damage and apoptotic cell death[J ] . Free Radic Biol Med, 2019, 141: 447-460. DOI:10.1016/j. freeradbiomed.2019.07.018.

ZHAN L, LI R, SUN Y H, et al . Effect of mito-TEMPO, a mitochondria-targeted antioxidant, in rats with neuropathic pain[J ] . Neuroreport, 2018, 29(15): 1275-1281. DOI:10.1097/ WNR.0000000000001105.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

缺氧后活化Drp1通过偶联LRRK2影响多组织细胞线粒体功能的机制研究

橘络黄酮对急性缺氧肠平滑肌细胞的保护作用

缺氧对PC12细胞中miR-210的表达及对细胞线粒体功能的影响

缺氧时肺动脉平滑肌细胞膜电位、细胞质及线粒体Ca²⁺的动态变化

缺氧复合运动大鼠心肌线粒体功能的变化