Twinkle 解旋酶的过表达可保护心肌细胞免受活性氧引起的遗传毒性应激。
Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species.
机构信息
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
出版信息
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19408-13. doi: 10.1073/pnas.1303046110. Epub 2013 Nov 11.
Abstract
Mitochondrial DNA (mtDNA) in adult human heart is characterized by complex molecular forms held together by junctional molecules of unknown biological significance. These junctions are not present in mouse hearts and emerge in humans during postnatal development, concomitant with increased demand for oxidative metabolism. To analyze the role of mtDNA organization during oxidative stress in cardiomyocytes, we used a mouse model, which recapitulates the complex mtDNA organization of human hearts by overexpression of the mitochondrial helicase, TWINKLE. Overexpression of TWINKLE rescued the oxidative damage induced replication stalling of mtDNA, reduced mtDNA point mutation load, and modified mtDNA rearrangements in heterozygous mitochondrial superoxide dismutase knockout hearts, as well as ameliorated cardiomyopathy in mice superoxide dismutase knockout in a p21-dependent manner. We conclude that mtDNA integrity influences cell survival and reason that tissue specific modes of mtDNA maintenance represent an adaptation to oxidative stress.
摘要
成人心脏中的线粒体 DNA（mtDNA）的特征是具有复杂的分子形式，这些分子形式由连接分子连接在一起，而这些连接分子的生物学意义尚不清楚。这些连接分子不存在于小鼠心脏中，而是在人类出生后发育过程中出现，与氧化代谢需求增加同时出现。为了分析 mtDNA 组织在心肌细胞氧化应激中的作用，我们使用了一种小鼠模型，该模型通过过度表达线粒体解旋酶 TWINKLE 来重现人类心脏中复杂的 mtDNA 组织。TWINKLE 的过表达挽救了 mtDNA 复制停滞引起的氧化损伤，降低了 mtDNA 点突变负荷，并改变了杂合子线粒体超氧化物歧化酶敲除心脏中的 mtDNA 重排，以及以 p21 依赖性方式改善了超氧化物歧化酶敲除小鼠的心肌病。我们得出结论，mtDNA 的完整性会影响细胞的存活，因此组织特异性的 mtDNA 维持模式代表了对氧化应激的适应。
相似文献
1
Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species.Twinkle 解旋酶的过表达可保护心肌细胞免受活性氧引起的遗传毒性应激。
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19408-13. doi: 10.1073/pnas.1303046110. Epub 2013 Nov 11.
2
Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress.TFAM或twinkle的过表达会增加线粒体DNA拷贝数，并促进与有限的线粒体氧化应激相关的心脏保护作用。
PLoS One. 2015 Mar 30;10(3):e0119687. doi: 10.1371/journal.pone.0119687. eCollection 2015.
3
TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication.TWINKLE 是一种必需的线粒体解旋酶，对于新生 D-loop 链的合成和完整 mtDNA 复制都是必需的。
Hum Mol Genet. 2013 May 15;22(10):1983-93. doi: 10.1093/hmg/ddt051. Epub 2013 Feb 7.
4
Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis.Twinkle过表达通过减轻线粒体生物合成受损来预防心肌梗死后心脏破裂。
Am J Physiol Heart Circ Physiol. 2016 Sep 1;311(3):H509-19. doi: 10.1152/ajpheart.00044.2016. Epub 2016 Jun 24.
5
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and chagasic patients: the role of Nrf1/2 and antioxidant response.线粒体 DNA 复制缺陷会在人类心肌细胞和恰加斯病患者感染克氏锥虫期间损害线粒体生物发生：Nrf1/2 和抗氧化反应的作用。
J Am Heart Assoc. 2012 Dec;1(6):e003855. doi: 10.1161/JAHA.112.003855. Epub 2012 Dec 19.
6
Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.动脉粥样硬化中，线粒体呼吸作用减弱，促进坏死核心形成并减小相对纤维帽厚度。
Arterioscler Thromb Vasc Biol. 2017 Dec;37(12):2322-2332. doi: 10.1161/ATVBAHA.117.310042. Epub 2017 Sep 28.
7
Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling.与常染色体显性进行性眼外肌麻痹相关的Twinkle突变导致解旋酶功能受损和体内线粒体DNA复制停滞。
Hum Mol Genet. 2009 Jan 15;18(2):328-40. doi: 10.1093/hmg/ddn359. Epub 2008 Oct 29.
8
TWINKLE and Other Human Mitochondrial DNA Helicases: Structure, Function and Disease.TWINKLE与其他人类线粒体DNA解旋酶：结构、功能与疾病
Genes (Basel). 2020 Apr 9;11(4):408. doi: 10.3390/genes11040408.
9
Stimulation of Variant Forms of the Mitochondrial DNA Helicase Twinkle by the Mitochondrial Single-Stranded DNA-Binding Protein.线粒体单链 DNA 结合蛋白对线粒体 DNA 解旋酶 Twinkle 变体形式的刺激。
Methods Mol Biol. 2021;2281:313-322. doi: 10.1007/978-1-0716-1290-3_20.
10
Developmental and pathological changes in the human cardiac muscle mitochondrial DNA organization, replication and copy number.人类心肌线粒体 DNA 组织、复制和拷贝数的发育和病理变化。
PLoS One. 2010 May 3;5(5):e10426. doi: 10.1371/journal.pone.0010426.
引用本文的文献
1
Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.过度活跃的线粒体 DNA 复制会破坏围产期心脏的成熟。
Nat Commun. 2024 Sep 14;15(1):8066. doi: 10.1038/s41467-024-52164-1.
2
Linear DNA-driven recombination in mammalian mitochondria.线性 DNA 驱动的哺乳动物线粒体重组。
Nucleic Acids Res. 2024 Apr 12;52(6):3088-3105. doi: 10.1093/nar/gkae040.
3
Structural and dynamic basis of DNA capture and translocation by mitochondrial Twinkle helicase.线粒体 Twinkle 解旋酶捕获和转位 DNA 的结构和动力学基础。
Nucleic Acids Res. 2022 Nov 11;50(20):11965-11978. doi: 10.1093/nar/gkac1089.
4
Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.线粒体DNA耗竭综合征及其相关心脏疾病。
Front Cardiovasc Med. 2022 Feb 14;8:808115. doi: 10.3389/fcvm.2021.808115. eCollection 2021.
5
Nuclear genome-wide associations with mitochondrial heteroplasmy.核基因组全基因组与线粒体异质性的关联。
Sci Adv. 2021 Mar 17;7(12). doi: 10.1126/sciadv.abe7520. Print 2021 Mar.
6
Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints.线粒体DNA缺失断点附近DNA杂交特征的热力学分析
iScience. 2021 Feb 4;24(3):102138. doi: 10.1016/j.isci.2021.102138. eCollection 2021 Mar 19.
7
Mutation of Gene Is One of the Reasons of Runting and Stunting Syndrome Characterized by mtDNA Depletion in Sex-Linked Dwarf Chicken.基因的突变是伴性矮小蛋鸡中以线粒体DNA耗竭为特征的矮小综合征的原因之一。
Front Cell Dev Biol. 2020 Jul 14;8:581. doi: 10.3389/fcell.2020.00581. eCollection 2020.
8
Cell Cycle Proteins as Key Regulators of Postmitotic Cell Death.细胞周期蛋白作为有丝分裂后细胞死亡的关键调节因子。
Yale J Biol Med. 2019 Dec 20;92(4):641-650. eCollection 2019 Dec.
9
Replication fork rescue in mammalian mitochondria.哺乳动物线粒体中复制叉的拯救。
Sci Rep. 2019 Jun 19;9(1):8785. doi: 10.1038/s41598-019-45244-6.
10
Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.恢复线粒体 DNA 拷贝数可维持线粒体功能并延缓小鼠血管衰老。
Aging Cell. 2018 Aug;17(4):e12773. doi: 10.1111/acel.12773. Epub 2018 May 9.
本文引用的文献
1
The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.Twinkle 解旋酶的过表达可改善压力超负荷模型中小鼠心脏纤维化和心力衰竭的进展。
PLoS One. 2013 Jun 28;8(6):e67642. doi: 10.1371/journal.pone.0067642. Print 2013.
2
Postnatal cardiomyocyte growth and mitochondrial reorganization cause multiple changes in the proteome of human cardiomyocytes.出生后心肌细胞的生长和线粒体重组导致人类心肌细胞蛋白质组发生多种变化。
Mol Biosyst. 2013 Jun;9(6):1210-9. doi: 10.1039/c3mb25556e. Epub 2013 Mar 4.
3
Two-dimensional intact mitochondrial DNA agarose electrophoresis reveals the structural complexity of the mammalian mitochondrial genome.二维完整线粒体 DNA 琼脂糖电泳揭示了哺乳动物线粒体基因组的结构复杂性。
Nucleic Acids Res. 2013 Feb 1;41(4):e58. doi: 10.1093/nar/gks1324. Epub 2012 Dec 28.
4
Detection of ultra-rare mutations by next-generation sequencing.通过下一代测序检测超罕见突变。
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14508-13. doi: 10.1073/pnas.1208715109. Epub 2012 Aug 1.
5
Oxidative stress during mitochondrial biogenesis compromises mtDNA integrity in growing hearts and induces a global DNA repair response.线粒体生物发生过程中的氧化应激会损害生长中心脏的 mtDNA 完整性，并诱导全局 DNA 修复反应。
Nucleic Acids Res. 2012 Aug;40(14):6595-607. doi: 10.1093/nar/gks301. Epub 2012 Apr 15.
6
Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.人线粒体 DNA 解旋酶 TWINKLE 既是解旋酶又是退火酶。
J Biol Chem. 2012 Apr 27;287(18):14545-56. doi: 10.1074/jbc.M111.309468. Epub 2012 Mar 1.
7
Increased mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA mutator mouse.肌肉中线粒体生物发生的增加改善了 mtDNA 突变小鼠的衰老表型。
Hum Mol Genet. 2012 May 15;21(10):2288-97. doi: 10.1093/hmg/dds049. Epub 2012 Feb 21.
8
Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.线粒体应激激活 E2F1 凋亡信号导致耳聋。
Cell. 2012 Feb 17;148(4):716-26. doi: 10.1016/j.cell.2011.12.027.
9
Mitochondrial complex I: a central regulator of the aging process.线粒体复合物 I：衰老过程的中央调控者。
Cell Cycle. 2011 May 15;10(10):1528-32. doi: 10.4161/cc.10.10.15496.
10
Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins.小鼠线粒体 DNA 的超高深度测序：突变模式及其起源。
PLoS Genet. 2011 Mar;7(3):e1002028. doi: 10.1371/journal.pgen.1002028. Epub 2011 Mar 24.
Zotero 插件