Rodrigues Tiago, Ferraz Letícia Silva
Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André, SP, Brazil.
Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André, SP, Brazil.
Biochem Pharmacol. 2020 Dec;182:114282. doi: 10.1016/j.bcp.2020.114282. Epub 2020 Oct 12.
In the past mitochondria were considered as the "powerhouse" of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.
过去，线粒体被认为是细胞的“动力源”，因为它们在有氧条件下通过氧化磷酸化产生超过90%的三磷酸腺苷（ATP）。然而，基于目前的认知，线粒体还发挥着其他多种细胞功能，包括参与钙稳态、自由基和活性氧的产生、触发/调节细胞凋亡等。此外，先前的发现认为线粒体是高度动态的结构，在活细胞内会发生形态改变，形成长片段或短片段。这个高度调控的过程被称为线粒体动力学，涉及线粒体融合和裂变。因此，线粒体的数量和线粒体网络的形态取决于线粒体动力学、生物发生和线粒体自噬。在每个细胞中，融合和裂变之间存在微妙的平衡，以维持适当的线粒体功能。有人提出，融合和裂变动力学过程控制细胞周期、代谢和存活，与广泛的生理和病理状况有关。线粒体融合由动力蛋白样蛋白介导，包括线粒体融合蛋白1（MFN1）、线粒体融合蛋白2（MFN2）和视神经萎缩1蛋白（OPA1）。相反，线粒体裂变会产生大量小片段，主要由动力相关蛋白1（DRP1）介导。有趣的是，越来越多的证据表明，肿瘤细胞会改变线粒体动力学的调节机制，以获得增殖和存活优势。在几种类型的人类癌细胞（黑色素瘤、卵巢癌、乳腺癌、肺癌、甲状腺癌、胶质母细胞瘤等）中都报道了线粒体裂变增加，一些研究还报道了线粒体融合增加与肿瘤细胞化疗耐药性之间可能存在直接关联。在此，将综述目前关于癌症中线粒体动力学改变的知识，并讨论其作为辅助癌症化疗靶点的潜力。
