The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity

• Published in: eLife Vol. 8
• Main Authors: Sirey, Tamara M, Roberts, Kenny, Haerty, Wilfried, Bedoya-Reina, Oscar, Rogatti-Granados, Sebastian, Tan, Jennifer Y, Li, Nick, Heather, Lisa C, Carter, Roderick N, Cooper, Sarah, Finch, Andrew J, Wills, Jimi, Morton, Nicholas M, Marques, Ana Claudia, Ponting, Chris P
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 02.05.2019; eLife Sciences Publications, Ltd
• Subjects: Animals; Biochemistry and Chemical Biology; Biosynthesis; Cell Line; Developmental biology; Electron transport chain; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; energy metabolism; Enzymatic activity; Enzymes; Gene Expression Profiling; Gene Expression Regulation; Genetics and Genomics; Genomes; Humans; Localization; long noncoding RNA; Mice; MicroRNAs - metabolism; miRNA; Mitochondria; Mitochondria - enzymology; NADH-ubiquinone oxidoreductase; Nervous system; Non-coding RNA; Oxidative phosphorylation; Oxidative stress; Phosphorylation; Post-transcription; post-transcriptional regulation; Protein transport; Proteins; Reactive oxygen species; Respiration; RNA, Long Noncoding - metabolism; Rotenone; Spinal cord; Stem cells; Stoichiometry; United Kingdom > UK; Germany; mouse; genetics; chemical biology; mitochondria; post-transcriptional regulation; biochemistry; long noncoding RNA; genomics; miRNA; human; energy metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.45051

To generate energy efficiently, the cell is uniquely challenged to co-ordinate the abundance of electron transport chain protein subunits expressed from both nuclear and mitochondrial genomes. How an effective stoichiometry of this many constituent subunits is co-ordinated post-transcriptionally remains poorly understood. Here we show that Cerox1 , an unusually abundant cytoplasmic long noncoding RNA (lncRNA), modulates the levels of mitochondrial complex I subunit transcripts in a manner that requires binding to microRNA-488-3p. Increased abundance of Cerox1 cooperatively elevates complex I subunit protein abundance and enzymatic activity, decreases reactive oxygen species production, and protects against the complex I inhibitor rotenone. Cerox1 function is conserved across placental mammals: human and mouse orthologues effectively modulate complex I enzymatic activity in mouse and human cells, respectively. Cerox1 is the first lncRNA demonstrated, to our knowledge, to regulate mitochondrial oxidative phosphorylation and, with miR-488-3p, represent novel targets for the modulation of complex I activity. Animal cells generate over 90% of the energy they need within small structures called mitochondria. Converting food into energy requires many different proteins and cells control the relative amounts of the proteins in mitochondria to ensure this process is efficient. To make more of a given protein, the cell must copy the DNA of the gene that encodes it into another molecule known as a messenger RNA, before reading the instructions in the messenger RNA to build the protein. However, this is not the only way that a cell uses molecules of RNA. A second group of RNAs called long non-coding RNAs (or lncRNAs) can help regulate the production of proteins in complex ways, and each lncRNA can have an effect across multiple genes. Some lncRNAs, for example, stop a third group of RNAs – microRNAs – from blocking certain messenger RNAs from being read. Sirey et al. set out to answer whether a lncRNA might help to co-ordinate the production of the many proteins needed by mitochondria. In experiments with mouse cells grown in the laboratory, Sirey et al. identified a lncRNA called Cerox1 that can co-ordinate the levels of at least 12 mitochondrial proteins. A microRNA called miR-488-3p suppresses the production of many of these proteins. By binding to miR-488-3p, Cerox1 blocks the effects of the microRNA so more proteins are produced. Sirey et al. artificially altered the amount of Cerox1 in the cells and showed that more Cerox1 leads to higher mitochondria activity. Further experiments revealed that this same control system also exists in human cells. Mitochondria are vital to cell survival and changes that affect their efficiency can be fatal or highly debilitating. Reduced efficiency is also a hallmark of ageing and contributes to conditions including cardiovascular disease, diabetes and Parkinson’s disease. Understanding how mitochondria are regulated could unlock new treatment methods for these conditions, while a better understanding of the co-ordination of protein production offers other insights into some of the most fundamental biology.