School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165523. doi: 10.1016/j.bbadis.2019.07.017. Epub 2019 Jul 31.
Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue that play a pivotal role in cutaneous wound healing by synthesizing fibronectin (a component of the extracellular matrix), secreting angiogenesis factors, and generating strong contractile forces. In wound healing, low concentrations of reactive oxygen species (ROS) are essential in combating invading microorganisms and in cell-survival signaling. However, excessive ROS production impairs fibroblasts. Mitochondrial NADP-dependent isocitrate dehydrogenase (IDH2) is a key enzyme that regulates the mitochondrial redox balance and reduces oxidative stress-induced cell injury through the generation of NADPH. In the present study, the downregulation of IDH2 expression resulted in an increase in cell apoptosis in mouse skin through ROS-dependent ATM-mediated p53 signaling. IDH2 deficiency also delayed cutaneous wound healing in mice and impaired dermal fibroblast function. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO alleviated the apoptosis induced by IDH2 deficiency both in vitro and in vivo. Together, our findings highlight the role of IDH2 in cutaneous wound healing in association with mitochondrial ROS.
真皮成纤维细胞是位于皮肤表皮和皮下组织之间的间充质细胞，通过合成纤维连接蛋白（细胞外基质的组成部分）、分泌血管生成因子和产生强大的收缩力，在皮肤伤口愈合中起着关键作用。在伤口愈合过程中，低浓度的活性氧（ROS）对于对抗入侵的微生物和细胞存活信号至关重要。然而，过量的 ROS 产生会损害成纤维细胞。线粒体 NADP 依赖性异柠檬酸脱氢酶（IDH2）是一种关键酶，可调节线粒体氧化还原平衡，并通过生成 NADPH 减少氧化应激诱导的细胞损伤。在本研究中，通过 ROS 依赖性 ATM 介导的 p53 信号通路，下调 IDH2 表达导致小鼠皮肤中成纤维细胞凋亡增加。IDH2 缺乏也延迟了小鼠的皮肤伤口愈合，并损害了真皮成纤维细胞的功能。此外，线粒体靶向抗氧化剂 mito-TEMPO 的预处理减轻了 IDH2 缺乏在体外和体内诱导的细胞凋亡。总之，我们的研究结果强调了 IDH2 在与线粒体 ROS 相关的皮肤伤口愈合中的作用。
