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

Abstract
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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

The following previously published data sets were used

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Article and author information

Author details

Tamara M Sirey

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

For correspondence
tamara.sirey@igmm.ed.ac.uk

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5606-2858
Kenny Roberts

MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6155-0821
Wilfried Haerty

MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Oscar Bedoya-Reina

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.
Sebastian Rogatti-Granados

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.
Jennifer Y Tan

MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Nick Li

MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Lisa C Heather

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Roderick N Carter

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.
Sarah Cooper

Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Andrew J Finch

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-8065-4623
Jimi Wills

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.
Nicholas M Morton

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
No competing interests declared.
Ana Claudia Marques

MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5174-8092
Chris P Ponting

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

For correspondence
Chris.Ponting@igmm.ed.ac.uk

Competing interests
Chris P Ponting, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0003-0202-7816

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

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.