Landowski Michael, Hagimori Ryo, Gogoi Purnima, Bhute Vijesh J, Ikeda Sakae, Takimoto Tetsuya, Ikeda Akihiro
Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
bioRxiv. 2025 May 26:2025.05.21.655403. doi: 10.1101/2025.05.21.655403.
Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these structures include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion in each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, along with their functional significance, are not well understood. Here, we investigate the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in shaping these structures and maintaining photoreceptor cell health. Rod photoreceptor cell-specific ablation of MFN1 and MFN2 resulted in mitochondrial fragmentation by one month of age, suggesting that mitochondrial fusion is essential for the development of photoreceptor cell-specific mitochondrial structures. Notably, the layer structures of the retina examined by light microscopy appeared unaffected at this age. Following this time period, significant photoreceptor cell degeneration occurred by three months of age. Furthermore, we showed that impaired mitochondrial fusion perturbed the balance of proteins involved in glycolysis, oxidative phosphorylation (OXPHOS), and β-oxidation, highlighting the critical role of mitochondrial fusion in ensuring the proper levels of proteins necessary for optimal energy metabolism. Additionally, we identified upregulation of cellular stress pathways such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which arise in response to energy deprivation, and cytoprotective biosynthetic pathways mediated by CCAAT/enhancer-binding protein gamma (C/EBPγ) and mammalian target of rapamycin complex 1 (mTORC1) signaling. In summary, our findings indicate that mitochondrial fusion through MFN1 and MFN2 is vital for the development of unique mitochondrial structures and proper energy production, underscoring the fundamental importance of mitochondrial dynamics in photoreceptor cell function and survival.
线粒体是动态细胞器，会经历持续的形态变化，但也展现出独特的、细胞类型特异性的结构。在视网膜的视杆光感受器细胞中，这些结构包括内段中的细长线粒体以及每个突触前末端中一个独特的、大的圆形线粒体。这些特殊线粒体形态的建立和维持机制及其功能意义尚未得到充分了解。在这里，我们研究线粒体融合蛋白线粒体融合蛋白1（MFN1）和线粒体融合蛋白2（MFN2）在塑造这些结构和维持光感受器细胞健康方面的作用。视杆光感受器细胞特异性敲除MFN1和MFN2会导致在一个月龄时线粒体碎片化，这表明线粒体融合对于光感受器细胞特异性线粒体结构的发育至关重要。值得注意的是，在这个年龄段，通过光学显微镜检查的视网膜层结构似乎未受影响。在此时间段之后，到三个月龄时发生了明显的光感受器细胞退化。此外，我们表明线粒体融合受损扰乱了参与糖酵解、氧化磷酸化（OXPHOS）和β-氧化的蛋白质平衡，突出了线粒体融合在确保最佳能量代谢所需蛋白质的适当水平方面的关键作用。此外，我们发现细胞应激途径如内质网（ER）应激和未折叠蛋白反应（UPR）上调，这些途径是在能量剥夺时出现的，以及由CCAAT/增强子结合蛋白γ（C/EBPγ）和雷帕霉素复合物1的哺乳动物靶标（mTORC1）信号介导的细胞保护生物合成途径。总之，我们的研究结果表明，通过MFN1和MFN2进行的线粒体融合对于独特线粒体结构的发育和适当的能量产生至关重要，强调了线粒体动力学在光感受器细胞功能和存活中的根本重要性。
