Defining the Role of Mitochondrial Fission in Corneal Myofibroblast Differentiation.
Defining the Role of Mitochondrial Fission in Corneal Myofibroblast Differentiation.
复制标题
DOI：
10.1167/iovs.63.4.2
复制
发表时间：
2022-04-01
影响因子：
4.4
通讯作者：
Huxlin KR
中科院分区：
文献类型：
--
作者：
Jeon KI;Kumar A;Wozniak KT;Nehrke K;Huxlin KR
角膜损伤引起的纤维化可导致瘢痕形成，损害视力。尽管阻止成纤维细胞向肌成纤维细胞分化具有治疗潜力，但其有效机制尚不明确。最近的研究表明，线粒体有助于几种组织的分化。在这里，我们验证了线粒体动力学，特别是裂变，是转化生长因子(TGF)-β1诱导的角膜肌成纤维细胞分化的关键的假设。体外培养的原代猫角膜成纤维细胞线粒体分裂受到抑制。我们测量了其对肌成纤维细胞分化分子标记的影响，并通过荧光成像评估了线粒体形态的变化。已建立的调节蛋白的磷酸化状态，无论是肌成纤维细胞分化和线粒体分裂，是由西方分析评估。线粒体裂变的药理抑制抑制了TGF-β1诱导的α -平滑肌肌动蛋白、胶原蛋白1和纤维连接蛋白表达的增加，并阻止了c-Jun n-末端激酶（JNK）的磷酸化，但对小母细胞对十五肢截瘫3、p38丝裂原活化蛋白激酶（p38）、细胞外信号调节激酶1 （ERK1）或蛋白激酶B （AKT）没有作用。TGF-β1增加线粒体裂变调节因子动力蛋白相关蛋白1 （DRP1）的磷酸化，导致线粒体网络断裂。尽管JNK、ERK1或AKT的抑制阻止了DRP1的磷酸化，但都不足以单独抑制TGF-β1诱导的断裂。线粒体动力学在早期角膜纤维形成中起关键作用，与纤维化信号一起起作用。这与线粒体作为协调代谢决策的信号中枢的作用是一致的。这表明一个前馈级联，通过线粒体，至少部分通过裂变，加强非规范TGF-β1信号，以实现角膜肌成纤维细胞分化。
Fibrosis caused by corneal wounding can lead to scar formation, impairing vision. Although preventing fibroblast-to-myofibroblast differentiation has therapeutic potential, effective mechanisms for doing so remain elusive. Recent work shows that mitochondria contribute to differentiation in several tissues. Here, we tested the hypothesis that mitochondrial dynamics, and specifically fission, are key for transforming growth factor (TGF)-β1–induced corneal myofibroblast differentiation. Mitochondrial fission was inhibited pharmacologically in cultured primary cat corneal fibroblasts. We measured its impact on molecular markers of myofibroblast differentiation and assessed changes in mitochondrial morphology through fluorescence imaging. The phosphorylation status of established regulatory proteins, both of myofibroblast differentiation and mitochondrial fission, was assessed by Western analysis. Pharmacological inhibition of mitochondrial fission suppressed TGF-β1-induced increases in alpha-smooth muscle actin, collagen 1, and fibronectin expression, and prevented phosphorylation of c-Jun N-terminal kinase (JNK), but not small mothers against decapentaplegic 3, p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase 1 (ERK1), or protein kinase B (AKT). TGF-β1 increased phosphorylation of dynamin-related protein 1 (DRP1), a mitochondrial fission regulator, and caused fragmentation of the mitochondrial network. Although inhibition of JNK, ERK1, or AKT prevented phosphorylation of DRP1, none sufficed to independently suppress TGF-β1–induced fragmentation. Mitochondrial dynamics play a key role in early corneal fibrogenesis, acting together with profibrotic signaling. This is consistent with mitochondria's role as signaling hubs that coordinate metabolic decision-making. This suggests a feed-forward cascade through which mitochondria, at least in part through fission, reinforce noncanonical TGF-β1 signaling to attain corneal myofibroblast differentiation.
登录
查看更多内容
TGF-β和活性氧的相互调节：纤维化的不良周期。
影响因子：
11.4
作者：
Liu RM;Desai LP
通讯作者：
Desai LP
影响因子：
3.9
作者：
Ding, Jie;Zhang, Zhihao;Wang, Dao Wen
通讯作者：
Wang, Dao Wen
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C
从受体到 Smads 的 TGF-β 信号传导
影响因子：
7.2
作者：
Hata A;Chen YG
通讯作者：
Chen YG
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi