Protective effect of the mitochondria-targeted antioxidant Mito-Tempo against acute liver injury in mice with sepsis

Xie Ke; Xu Fang

doi:10.13406/j.cnki.cyxb.003475

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Protective effect of the mitochondria-targeted antioxidant Mito-Tempo against acute liver injury in mice with sepsis

Basic research | 更新时间：2025-10-22

- Protective effect of the mitochondria-targeted antioxidant Mito-Tempo against acute liver injury in mice with sepsis
- Journal of Chongqing Medical University Vol. 49, Issue 4, Pages: 428-435(2024)
- 作者机构：
  
  重庆医科大学附属第一医院重症医学科，重庆　400016
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003475
  CLC： R575
- Received：12 March 2024，
  
  Revised：2024-03-29，
  
  Accepted：07 April 2024，
  
  Published：28 April 2024
- 稿件说明：
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谢珂,徐昉.线粒体靶向抗氧化剂Mito-Tempo对脓毒症小鼠急性肝损伤的保护作用[J].重庆医科大学学报,2024,49(4):428-435.

Xie Ke,Xu Fang.Protective effect of the mitochondria-targeted antioxidant Mito-Tempo against acute liver injury in mice with sepsis[J].Journal of Chongqing Medical University,2024,49(4):428-435.
谢珂,徐昉.线粒体靶向抗氧化剂Mito-Tempo对脓毒症小鼠急性肝损伤的保护作用[J].重庆医科大学学报,2024,49(4):428-435. DOI： 10.13406/j.cnki.cyxb.003475.

Xie Ke,Xu Fang.Protective effect of the mitochondria-targeted antioxidant Mito-Tempo against acute liver injury in mice with sepsis[J].Journal of Chongqing Medical University,2024,49(4):428-435. DOI： 10.13406/j.cnki.cyxb.003475.

摘要

目的

探讨线粒体靶向抗氧化剂Mito-Tempo对脓毒症小鼠急性肝损伤的影响及可能机制。

方法

将C57BL/6小鼠随机分为对照组（Control组）、盲肠结扎穿刺组（CLP组）、Mito-Tempo治疗组（CLP+Mito-Tempo组）。采用盲肠结扎穿刺术（cecal ligation and puncture，CLP）构建小鼠脓毒症急性肝损伤模型，CLP+Mito-Tempo组在CLP处理前1 h使用Mito-Tempo腹腔注射进行预处理。24 h后麻醉并处死小鼠，取小鼠肝脏组织进行HE染色观察肝组织病理损伤；ELISA法监测血清中炎症因子，免疫荧光染色检测肝组织中活性氧（reactive oxygen species，ROS）的水平；电镜观察线粒体形态，Western blot法检测细胞焦亡相关蛋白剪切型含半胱氨酸的天冬氨酸蛋白水解酶-1（cleaved cysteinyl aspartate specific proteinase 1，cleaved-Caspases-1）、剪切型焦孔素D（cleaved-gasdermin D，GSDMD）、白细胞介素-1α（interleukin 1α，IL-1α）、白细胞介素-1β（interleukin 1β，IL-1β）的表达水平。

结果

与Control组相比，CLP组肝损伤加重，ROS水平增加，线粒体形态出现破坏，细胞焦亡相关蛋白cleaved-Caspase-1、cleaved-GSDMD、IL-1α、IL-1β的表达水平增加；与CLP组相比，CLP+Mito-Tempo组肝组织损伤程度减轻，ROS水平降低，线粒体形态部分恢复，细胞焦亡相关蛋白cleaved-Caspase-1、cleaved-GSDMD、IL-1α、IL-1β的表达水平降低。

结论

Mito-Tempo可以减轻脓毒症小鼠急性肝损伤，其机制可能与降低氧化应激水平抑制细胞焦亡的发生有关。

Abstract

Objective

To investigate the effect of the mitochondria-targeted antioxidant Mito-Tempo on acute liver injury in mice with sepsis and its possible mechanisms.

Methods

C57BL/6 mice were randomly divided into control group（Control group），cecal ligation puncture group（CLP group），and Mito-Tempo treatment group（CLP+Mito-Tempo group）. Cecal ligation and puncture（CLP） was used to establish a mouse model of sepsis and acute liver injury，and the mice in the CLP+Mito-Tempo group were pretreated with intraperitoneal injection of Mito-Tempo at 1 hour before CLP treatment. After 24 hours，the mice were anesthetized and sacrificed，and HE staining was used to observe liver histopathological injury；ELISA was used to measure the serum levels of inflammatory factors，and immunofluorescent staining was used to measure the level of reactive oxygen species（ROS） in liver tissue；an electron microscope was used to observe the morphology of mitochondria；Western blot was used to measure the expression levels of cleaved cysteinyl aspartate specific proteinase 1（cleaved caspase-1），cleaved gasdermin D（GSDMD），interleukin-1α（IL-1α），and interleukin-1β（IL-1β）.

Results

Compared with the Control group，the CLP group had aggravation of liver injury，an increase in ROS level，destroyed mitochondrial morphology，and increases in the expression levels of the pyroptosis-related proteins cleaved caspase-1，cleaved GSDMD，IL-1α，and IL-1β. Compared with the CLP group，the CLP+Mito-Tempo group had alleviation of liver injury，a reduction in ROS level，partial restoration of mitochondrial morphology，and significant reductions in the expression levels of the pyroptosis-related proteins cleaved caspase-1，cleaved GSDMD，IL-1α，and IL-1β.

Conclusion

Mito-Tempo can alleviate acute liver injury in mice with sepsis，possibly by reducing the level of oxidative stress and inhibiting pyroptosis.

关键词

Keywords

references

Liu D ， Huang SY ， Sun JH ， et al . Sepsis-induced immunosuppression：mechanisms，diagnosis and current treatment options [J ] . Mil Med Res ， 2022 ， 9 （ 1 ）： 56 ．

Xiao LX ， Qi L ， Zhang GZ ， et al . Polygonatum sibiricum polysaccharides attenuate lipopoly-saccharide-induced septic liver injury by suppression of pyroptosis via NLRP3/GSDMD signals [J ] . Molecules ， 2022 ， 27 （ 18 ）： 5999 .

Yan J ， Li S ， Li SL . The role of the liver in sepsis [J ] . Int Rev Immunol ， 2014 ， 33 （ 6 ）： 498 - 510 .

Luo XY ， Jiang XK ， Li J ， et al . Insulin-like growth factor-1 attenuates oxidative stress-induced hepatocyte premature senescence in liver fibrogenesis via regulating nuclear p53-progerin interaction [J ] . Cell Death Dis ， 2019 ， 10 （ 6 ）： 451 .

Ge WH ， Wang T ， Zhao Y ， et al . Period1 mediates rhythmic metabolism of toxins by interacting with CYP2E1 [J ] . Cell Death Dis ， 2021 ， 12 （ 1 ）： 76 ．

Li L ， Cui YJ ， Liu Y ， et al . ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation [J ] . Cell Death Discov ， 2022 ， 8 （ 1 ）： 161 .

Xue ZY ， Xi Q ， Liu HK ， et al . miR-21 promotes NLRP3 inflammasome activation to mediate pyroptosis and endotoxic shock [J ] . Cell Death Dis ， 2019 ， 10 （ 6 ）： 461 .

Weinberg SE ， Chandel NS . Targeting mitochondria metabolism for cancer therapy [J ] . Nat Chem Biol ， 2015 ， 11 （ 1 ）： 9 - 15 .

Dominic A ， Hamilton D ， Abe JI . Mitochondria and chronic effects of cancer therapeutics：the clinical implications [J ] . J Thromb Thrombolysis ， 2021 ， 51 （ 4 ）： 884 - 889 .

Yu HC ， Hou GW ， Cao JK ， et al . Mangiferin alleviates mitochondrial ROS in nucleus pulposus cells and protects against intervertebral disc degeneration via suppression of NF- κ B signaling pathway [J ] . Oxid Med Cell Longev ， 2021 ， 2021 ： 6632786 .

Li XY ， Fang P ， Mai JT ， et al . Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers [J ] . J Hematol Oncol ， 2013 ， 6 ： 19 ．

Wen JJ ， Williams TP ， Cummins CB ， et al . Effect of mitochondrial antioxidant（mito-TEMPO） on burn-induced cardiac dysfunction [J ] . J Am Coll Surg ， 2021 ， 232 （ 4 ）： 642 - 655 ．

Ding W ， Guo HL ， Xu CY ， et al . Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury [J ] . Oncotarget ， 2016 ， 7 （ 14 ）： 17479 - 17491 .

Taylor MD ， Fernandes TD ， Kelly AP ， et al . CD4 and CD8 T cell memory interactions alter innate immunity and organ injury in the CLP sepsis model [J ] . Front Immunol ， 2020 ， 11 ： 563402 ．

Heijnen BH ， Straatsburg IH ， Gouma DJ ， et al . Decrease in core liver temperature with 10 degrees C by in situ hypothermic perfusion under total hepatic vascular exclusion reduces liver ischemia and reperfusion injury during partial hepatectomy in pigs [J ] . Surgery ， 2003 ， 134 （ 5 ）： 806 - 817 .

Silwal P ， Kim JK ， Kim YJ ， et al . Mitochondrial reactive oxygen species：double-edged weapon in host defense and pathological inflammation during infection [J ] . Front Immunol ， 2020 ， 11 ： 1649 .

Abdullah-Al-Shoeb M ， Sasaki K ， Kikutani S ， et al . The late-stage protective effect of mito-TEMPO against acetaminophen-induced hepatotoxicity in mouse and three-dimensional cell culture models [J ] . Antioxidants ， 2020 ， 9 （ 10 ）： 965 .

Patil NK ， Parajuli N ， MacMillan-Crow LA ， et al . Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis：mitochondria-targeted antioxidant mitigates injury [J ] . Am J Physiol Renal Physiol ， 2014 ， 306 （ 7 ）： F734 - F743 .

Rocha VC ， França LS ， de Araújo CF ， et al . Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice [J ] . Cancer Chemother Pharmacol ， 2016 ， 77 （ 3 ）： 659 - 662 .

Li Q ， Zhang W ， Cheng N ， et al . Pectolinarigenin ameliorates acetaminophen-induced acute liver injury via attenuating oxidative stress and inflammatory response in Nrf2 and PPARa dependent manners [J ] . Phytomedicine ， 2023 ， 113 ： 154726 .

Xia T ， Zhang J ， Yao JH ， et al . Shanxi aged vinegar protects against alcohol-induced liver injury via activating Nrf2-mediated antioxidant and inhibiting TLR4-induced inflammatory response [J ] . Nutrients ， 2018 ， 10 （ 7 ）： 805 .

Chen L ， Zhu YQ ， Zhou J ， et al . Luteolin alleviates epithelial-mesenchymal transformation induced by oxidative injury in ARPE-19 cell via Nrf2 and AKT/GSK-3 β pathway [J ] . Oxid Med Cell Longev ， 2022 ， 2022 ： 2265725 .

Lin WC ， Chen CW ， Huang YW ， et al . Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis [J ] . Sci Rep ， 2015 ， 5 ： 12463 .

Liao Y ， Lin X ， Li JC ， et al . Nodakenin alleviates renal ischaemia-reperfusion injury via inhibiting reactive oxygen species-induced NLRP3 inflammasome activation [J ] . Nephrology ， 2021 ， 26 （ 1 ）： 78 - 87 .

Wu AG ， Zhou XG ， Qiao G ， et al . Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases [J ] . Ageing Res Rev ， 2021 ， 65 ： 101202 .

Wang YY ， Wang M ， Liu YS ， et al . Integrated regulation of stress responses，autophagy and survival by altered intracellular iron stores [J ] . Redox Biol ， 2022 ， 55 ： 102407 .

Sandoval C ， Mella L ， Godoy K ， et al . β-carotene increases activity of cytochrome P450 2E1 during ethanol consumption [J ] . Antioxidants ， 2022 ， 11 （ 5 ）： 1033 .

Coll RC ， Schroder K ， Pelegrín P . NLRP3 and pyroptosis blockers for treating inflammatory diseases [J ] . Trends Pharmacol Sci ， 2022 ， 43 （ 8 ）： 653 - 668 .

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