The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity
- University of Edinburgh, United Kingdom
- University of Oxford, United Kingdom
Abstract
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.
Data availability
Microarray data are available through ArrayExpress, accession code E-MATB-6792
Article and author information
Author details
Ana Claudia Marques
Funding
Wellcome (WT106956/Z/15/Z)
- Tamara M Sirey
- Oscar Bedoya-Reina
- Sebastian Rogatti-Granados
- Chris P Ponting
European Research Council (249869)
- Tamara M Sirey
- Kenny Roberts
- Ana Claudia Marques
- Chris P Ponting
Wellcome (WT100981/z/13/z)
- Roderick N Carter
- Nicholas M Morton
Medical Research Council
- Wilfried Haerty
- Chris P Ponting
Diabetes UK
- Lisa C Heather
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Sirey et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity
eLife 8:e45051.
https://doi.org/10.7554/eLife.45051
Further reading
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- Biochemistry and Chemical Biology
Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here, we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3’-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3’ overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.
