杜氏肌营养不良症晚期的线粒体生成过程揭示了一种对氧化还原反应敏感的肌酸通路,线粒体靶向肽 SBT-20 可以增强这种通路的功能

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
{"title":"杜氏肌营养不良症晚期的线粒体生成过程揭示了一种对氧化还原反应敏感的肌酸通路,线粒体靶向肽 SBT-20 可以增强这种通路的功能","authors":"","doi":"10.1016/j.redox.2024.103319","DOIUrl":null,"url":null,"abstract":"<div><p>Mitochondrial creatine kinase (mtCK) regulates the “fast” export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such “creatine-dependent” phosphate shuttling is attenuated in several muscles, including the heart, of the D2.<em>mdx</em> mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.<em>mdx</em> (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.<em>mdx</em> mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H<sub>2</sub>O<sub>2</sub> emission (mH<sub>2</sub>O<sub>2</sub>). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH<sub>2</sub>O<sub>2</sub> was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4–∼12 weeks of age) increased respiration and lowered mH<sub>2</sub>O<sub>2</sub> only in the presence of creatine in D2.<em>mdx</em> mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.<em>mdx</em> mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7000,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002970/pdfft?md5=80166a119caa767e3f5f20e04638d7a4&pid=1-s2.0-S2213231724002970-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20\",\"authors\":\"\",\"doi\":\"10.1016/j.redox.2024.103319\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Mitochondrial creatine kinase (mtCK) regulates the “fast” export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such “creatine-dependent” phosphate shuttling is attenuated in several muscles, including the heart, of the D2.<em>mdx</em> mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.<em>mdx</em> (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.<em>mdx</em> mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H<sub>2</sub>O<sub>2</sub> emission (mH<sub>2</sub>O<sub>2</sub>). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH<sub>2</sub>O<sub>2</sub> was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4–∼12 weeks of age) increased respiration and lowered mH<sub>2</sub>O<sub>2</sub> only in the presence of creatine in D2.<em>mdx</em> mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.<em>mdx</em> mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.</p></div>\",\"PeriodicalId\":20998,\"journal\":{\"name\":\"Redox Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.7000,\"publicationDate\":\"2024-08-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2213231724002970/pdfft?md5=80166a119caa767e3f5f20e04638d7a4&pid=1-s2.0-S2213231724002970-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Redox Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2213231724002970\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Redox Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213231724002970","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

线粒体肌酸激酶(mtCK)调节磷酸肌酸的 "快速 "输出,以支持细胞质中的 ADP 磷酸化为 ATP,这种磷酸化比直接输出 ATP 更快。这种 "依赖肌酸 "的磷酸盐穿梭在 D2.杜氏肌营养不良症小鼠模型的几块肌肉(包括心脏)中,在其 4 周大时就会减弱。然而,在整个疾病进展过程中,依赖肌酸和不依赖肌酸的磷酸盐穿梭系统在多大程度上会逐渐恶化或可能以激素方式进行调整,目前仍是未知数。在此,我们进行了一系列原理验证研究,旨在确定磷酸盐转运途径在 D2.(12个月大)。我们还确定了肌酸依赖性磷酸盐穿梭的变化是否与肌酸激酶硫醇氧化还原状态的改变有关。在从左心室制备的透化肌纤维中,我们发现 12 个月大的雄性 D2.小鼠肌酸依赖性丙酮酸氧化作用降低,复合物 I 支持的 HO 发射(mHO)升高。令人惊讶的是,肌酸依赖性 ADP 刺激的呼吸增加了,而 mHO 却降低了,这表明 mtCK 介导的较快磷酸肌酸输出系统的损伤导致了替代性较慢 ATP 输出途径的补偿。依赖于 mtCK 的生物能明显受损与 mtCK 蛋白含量无关,但与 mtCK 的硫醇氧化程度更高以及细胞环境氧化程度更高(GSH:GSSG 更低)有关。接下来,我们进行了一项原理验证研究,以确定是否可以通过长期服用线粒体靶向、降低 ROS 的四肽 SBT-20 来增强肌酸依赖性生物能。我们发现,D2.小鼠在肌酸存在的情况下,每天服用 SBT-20(从 4∼12 周龄开始)12 周后,呼吸增加,mHO 降低,而钙诱导的线粒体通透性转换活性不受影响。总之,依赖肌酸的线粒体生物能在年龄较大的 D2.小鼠中减弱,这与 mtCK 硫醇氧化有关,而依赖肌酸的磷酸盐穿梭作为一种独特的线粒体生成形式,似乎被增加的肌酸所抵消。另外的研究结果表明,依赖肌酸的生物能也可以通过降低 ROS 的线粒体靶向肽来增强。这些结果表明,在肌营养不良症过程中,氧化还原压力与线粒体激素重编程之间存在特殊关系,并证明了肌酸依赖性生物能可通过线粒体靶向小肽疗法来改变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20

Mitochondrial creatine kinase (mtCK) regulates the “fast” export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such “creatine-dependent” phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.mdx (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.mdx mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H2O2 emission (mH2O2). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH2O2 was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4–∼12 weeks of age) increased respiration and lowered mH2O2 only in the presence of creatine in D2.mdx mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.mdx mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信