Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Elife. 2020 Jan 15;9:e50705. doi: 10.7554/eLife.50705.
Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5'UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5'UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.
高效的线粒体功能是高能量需求组织所必需的，如心脏，而线粒体功能障碍与心血管疾病有关。线粒体蛋白的表达受到内部和外部刺激的严格调控。在这里，我们发现了一种通过 BUD23 依赖性核糖体生成来调节线粒体含量和功能的新机制。BUD23 对于核糖体成熟、正常的 18S/28S 比例以及在人 A549 细胞中转录线粒体转录本的翻译都是必需的。在鼠心肌细胞中删除会减少线粒体含量和功能，导致严重的心肌病和死亡。我们发现 BUD23 选择性地促进核糖体与低 GC 含量 5'UTR 的相互作用。总之，我们确定 BUD23 通过促进低 5'UTR GC 含量的 mRNA 转录本的有效翻译，在生物能量基因表达中发挥关键作用。BUD23 对于小鼠的发育以及出生后的心脏功能是必不可少的。
