Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Department of Physics, University of South Florida, Tampa, FL 33620, USA.
Cells. 2021 May 14;10(5):1202. doi: 10.3390/cells10051202.
In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.
在心脏中，线粒体稳态对于维持正常功能和对代谢及环境应激因子的最佳反应至关重要。线粒体融合和裂变被认为对于维持大量的线粒体是必要的，而线粒体裂变和/或融合的破坏可导致细胞功能障碍。与动力蛋白相关的蛋白（DRP1）是线粒体裂变的重要介质。在这项研究中，我们使用 Western blot、共聚焦和透射电子显微镜以及使用随机建模的线粒体网络定量分析，研究了微量营养素视黄醇全反式视黄酸（ATRA）对体内和体外线粒体结构的直接影响。我们的结果表明，ATRA 增加 DRP1 蛋白水平，并增加分离的线粒体制剂中 DRP1 向线粒体的定位。我们的结果还表明，ATRA 重塑了线粒体超微结构，其中线粒体面积和周长减小，而圆度增加。从显微镜上看，正如我们的数值模型所表明的那样，线粒体网络重塑是由 ATRA 中裂变事件相对于融合事件的增加速率驱动的。总之，ATRA 导致 DRP1 蛋白的药理学介导增加。它还通过促进裂变事件来调节心脏线粒体，改变线粒体网络，并修饰心脏中线粒体的超微结构。
