Mechanisms of mitochondrial resilience in teleostean radial glia under hypoxic stress

IF 3.9 3区 环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Comparative Biochemistry and Physiology C-toxicology & Pharmacology Pub Date : 2024-08-14 DOI:10.1016/j.cbpc.2024.110001
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Abstract

Radial glial cells (RGCs) are remarkable cells, essential for normal development of the vertebrate central nervous system. In teleost fishes, RGCs play a pivotal role in neurogenesis and regeneration of injured neurons and glia. RGCs also exhibit resilience to environmental stressors like hypoxia via metabolic adaptations. In this study, we assessed the physiology of RGCs following varying degrees of hypoxia, with an emphasis on reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitophagy, and energy metabolism. Our findings demonstrated that hypoxia significantly elevated ROS production and induced MMP depolarization in RGCs. The mitochondrial disturbances were closely associated with increased mitophagy, based on the co-localization of mitochondria and lysosomes. Key mitophagy-related genes were also up-regulated, including those of the BNIP3/NIX mediated pathway as well as the FUNDC1 mediated pathway. Such responses suggest robust cellular mechanisms are initiated to counteract mitochondrial damage due to increasing hypoxia. A significant metabolic shift from oxidative phosphorylation to glycolysis was also observed in RGCs, which may underlie an adaptive response to sustain cellular function and viability following a reduction in oxygen availability. Furthermore, hypoxia inhibited the synthesis of mitochondrial complexes subunits in RGCs, potentially related to elevated HIF-2α expression with 3 % O2. Taken together, RGCs appear to exhibit complex adaptive responses to hypoxic stress, characterized by metabolic reprogramming and the activation of mitophagy pathways to mitigate mitochondrial dysfunction.

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缺氧胁迫下桡神经胶质细胞线粒体的恢复机制
放射状神经胶质细胞(RGC)是脊椎动物中枢神经系统正常发育必不可少的重要细胞。在远洋鱼类中,RGCs 在神经发生以及受伤神经元和神经胶质的再生过程中发挥着关键作用。RGCs 还能通过新陈代谢适应缺氧等环境压力而表现出恢复能力。在这项研究中,我们评估了不同程度缺氧后 RGCs 的生理状况,重点是活性氧(ROS)生成、线粒体膜电位(MMP)、有丝分裂和能量代谢。我们的研究结果表明,缺氧会显著增加 ROS 的产生,并诱导 RGC 的线粒体膜电位去极化。根据线粒体和溶酶体的共定位,线粒体紊乱与有丝分裂的增加密切相关。与有丝分裂相关的关键基因也被上调,包括 BNIP3/NIX 介导的途径和 FUNDC1 介导的途径。这些反应表明,细胞启动了强大的机制来抵消因缺氧加剧而造成的线粒体损伤。在 RGCs 中还观察到从氧化磷酸化到糖酵解的重大代谢转变,这可能是氧气供应减少后维持细胞功能和活力的适应性反应的基础。此外,缺氧抑制了 RGC 中线粒体复合物亚基的合成,这可能与 3%O2 时 HIF-2α 表达的升高有关。总之,RGCs 似乎对缺氧压力表现出复杂的适应性反应,其特点是代谢重编程和激活有丝分裂途径以缓解线粒体功能障碍。
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来源期刊
CiteScore
7.50
自引率
5.10%
发文量
206
审稿时长
30 days
期刊介绍: Part C: Toxicology and Pharmacology. This journal is concerned with chemical and drug action at different levels of organization, biotransformation of xenobiotics, mechanisms of toxicity, including reactive oxygen species and carcinogenesis, endocrine disruptors, natural products chemistry, and signal transduction with a molecular approach to these fields.
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