Department of Biology, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5, Canada.
Sci Rep. 2022 Apr 2;12(1):5576. doi: 10.1038/s41598-022-09374-8.
Goldfish enter a hypometabolic state to survive chronic hypoxia. We recently described tissue-specific contributions of membrane lipid composition remodeling and mitochondrial function to metabolic suppression across different goldfish tissues. However, the molecular and especially epigenetic foundations of hypoxia tolerance in goldfish under metabolic suppression are not well understood. Here we show that components of the molecular oxygen-sensing machinery are robustly activated across tissues irrespective of hypoxia duration. Induction of gene expression of enzymes involved in DNA methylation turnover and microRNA biogenesis suggest a role for epigenetic transcriptional and post-transcriptional suppression of gene expression in the hypoxia-acclimated brain. Conversely, mechanistic target of rapamycin-dependent translational machinery activity is not reduced in liver and white muscle, suggesting this pathway does not contribute to lowering cellular energy expenditure. Finally, molecular evidence supports previously reported chronic hypoxia-dependent changes in membrane cholesterol, lipid metabolism and mitochondrial function via changes in transcripts involved in cholesterol biosynthesis, β-oxidation, and mitochondrial fusion in multiple tissues. Overall, this study shows that chronic hypoxia robustly induces expression of oxygen-sensing machinery across tissues, induces repressive transcriptional and post-transcriptional epigenetic marks especially in the chronic hypoxia-acclimated brain and supports a role for membrane remodeling and mitochondrial function and dynamics in promoting metabolic suppression.
金鱼进入低代谢状态以在慢性缺氧环境中生存。我们最近描述了膜脂组成重塑和线粒体功能在金鱼不同组织中的代谢抑制作用的组织特异性贡献。然而，在代谢抑制下金鱼对缺氧的耐受的分子，特别是表观遗传基础还不是很清楚。在这里，我们显示出分子氧感应机制的组成部分在不同的缺氧持续时间下在所有组织中都被强烈激活。参与 DNA 甲基化周转和 microRNA 生物发生的酶的基因表达诱导表明，表观遗传转录和转录后抑制基因表达在缺氧适应的大脑中发挥作用。相反，在肝脏和白色肌肉中，雷帕霉素靶蛋白依赖性翻译机制的活性并没有降低，这表明该途径不会降低细胞能量消耗。最后，分子证据支持了先前报道的慢性缺氧依赖性改变，通过涉及胆固醇生物合成、β-氧化和线粒体融合的转录本的改变，改变了膜胆固醇、脂质代谢和线粒体功能在多个组织中的作用。总的来说，这项研究表明，慢性缺氧在所有组织中都强烈诱导了氧感应机制的表达，在慢性缺氧适应的大脑中诱导了抑制性的转录和转录后表观遗传标记，并支持了膜重塑和线粒体功能和动力学在促进代谢抑制中的作用。
