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.
Reviewing Editor
- Detlef Weigel, Max Planck Institute for Developmental Biology, Germany
Version history
- Received: January 10, 2019
- Accepted: May 2, 2019
- Accepted Manuscript published: May 2, 2019 (version 1)
- Version of Record published: May 30, 2019 (version 2)
- Version of Record updated: August 12, 2019 (version 3)
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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Mediator of ERBB2-driven Cell Motility 1 (MEMO1) is an evolutionary conserved protein implicated in many biological processes; however, its primary molecular function remains unknown. Importantly, MEMO1 is overexpressed in many types of cancer and was shown to modulate breast cancer metastasis through altered cell motility. To better understand the function of MEMO1 in cancer cells, we analyzed genetic interactions of MEMO1 using gene essentiality data from 1028 cancer cell lines and found multiple iron-related genes exhibiting genetic relationships with MEMO1. We experimentally confirmed several interactions between MEMO1 and iron-related proteins in living cells, most notably, transferrin receptor 2 (TFR2), mitoferrin-2 (SLC25A28), and the global iron response regulator IRP1 (ACO1). These interactions indicate that cells with high MEMO1 expression levels are hypersensitive to the disruptions in iron distribution. Our data also indicate that MEMO1 is involved in ferroptosis and is linked to iron supply to mitochondria. We have found that purified MEMO1 binds iron with high affinity under redox conditions mimicking intracellular environment and solved MEMO1 structures in complex with iron and copper. Our work reveals that the iron coordination mode in MEMO1 is very similar to that of iron-containing extradiol dioxygenases, which also display a similar structural fold. We conclude that MEMO1 is an iron-binding protein that modulates iron homeostasis in cancer cells.
