The human mitochondrial mRNA structurome reveals mechanisms of gene expression

• 成果类型: Article
• 署名作者: Moran, J. Conor; Brivanlou, Amir; Brischigliaro, Michele; Fontanesi, Flavia; Rouskin, Silvi; Barrientos, Antoni
• 署名单位: University of Miami; University of Miami; Harvard University; Harvard Medical School; University of Miami
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8745
• DOI: 10.1126/science.adm9238
• 发表日期: 2024-07-19
• 关键词: cytochrome-c-oxidase; secondary structure; translation initiation; ribosome; polyadenylation; identification; reinitiation; RECOGNITION; involvement; termination

摘要

The human mitochondrial genome encodes crucial oxidative phosphorylation system proteins, pivotal for aerobic energy transduction. They are translated from nine monocistronic and two bicistronic transcripts whose native structures remain unexplored, posing a gap in understanding mitochondrial gene expression. In this work, we devised the mitochondrial dimethyl sulfate mutational profiling with sequencing (mitoDMS-MaPseq) method and applied detection of RNA folding ensembles using expectation-maximization (DREEM) clustering to unravel the native mitochondrial messenger RNA (mt-mRNA) structurome in wild-type (WT) and leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)-deficient cells. Our findings elucidate LRPPRC's role as a holdase contributing to maintaining mt-mRNA folding and efficient translation. mt-mRNA structural insights in WT mitochondria, coupled with metabolic labeling, unveil potential mRNA-programmed translational pausing and a distinct programmed ribosomal frameshifting mechanism. Our data define a critical layer of mitochondrial gene expression regulation. These mt-mRNA folding maps provide a reference for studying mt-mRNA structures in diverse physiological and pathological contexts.