Gravitational and mechanical forces drive mitochondrial translation - mouse datasets

Life on Earth has evolved in a form suitable for the gravitational force of 1 x g. Although the pivotal role of gravity in gene expression has been revealed by multi-omics approaches in space-flown samples and astronauts, the molecular details of how mammalian cells harness gravity have remained unclear. Here, we showed that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling revealed reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under both microgravity at the International Space Station and simulated microgravity in a 3D-clinostat on the ground. We found that attenuation of cell adhesion through laminin-integrin interactions causes the phenotype. The downstream signaling pathway including FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix maintain mitochondrial translation at high level. Mechanistically, a decreased level of mitochondrial malonyl-CoA, which is consumed by activated mtFAS, leads to a reduction in the malonylation of the translational machinery and an increase in the initiation and elongation of in organello translation. Consistent with the role of integrin as a mechanosensor, we observed a decrease in mitochondrial translation via the minimization of mechanical stress in mouse skeletal muscle. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in an energy-producing organelle. This study hosts the mouse datasets. The human HEK293 cell datasets are available in OSD-936, and the C. elegans (nematode) datasets are available in OSD-956.

地球上的生命演化出了适配1×g重力的形态。尽管借助太空飞行样本与宇航员样本的多组学研究，已揭示重力在基因表达中的关键作用，但哺乳动物细胞如何利用重力的分子机制仍未明确。本研究发现，线粒体可利用重力激活细胞器内的蛋白质合成。全基因组核糖体图谱（ribosome profiling）分析显示，在国际空间站（International Space Station）的微重力环境与地面3D回转器（3D-clinostat）模拟的微重力环境中，哺乳动物细胞与秀丽隐杆线虫（Caenorhabditis elegans）的线粒体翻译水平均出现下调。我们发现，通过层粘连蛋白-整合素（laminin-integrin）相互作用减弱细胞黏附，会引发该表型。胞质中包含FAK、RAC1、PAK1、BAD及Bcl-2家族蛋白的下游信号通路，以及线粒体基质中的线粒体脂肪酸合成（mitochondrial fatty acid synthesis, mtFAS）通路，共同维持高水平的线粒体翻译。从机制层面来看，被激活的mtFAS所消耗的线粒体丙二酰-CoA水平降低，会导致翻译机器的丙二酰化修饰水平下降，并提升细胞器内翻译的起始与延伸效率。与整合素作为机械传感器的功能相符，我们在小鼠骨骼肌中观察到，通过最小化机械应力可降低线粒体翻译水平。本研究为细胞如何将重力与机械力转化为产能细胞器内的翻译过程提供了机制层面的见解。本研究附带小鼠数据集，人类HEK293细胞数据集可于OSD-936获取，秀丽隐杆线虫（线虫）数据集可于OSD-956获取。