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

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5606-2858
  2. Kenny Roberts

    MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6155-0821
  3. Wilfried Haerty

    MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. 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.
  5. 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.
  6. Jennifer Y Tan

    MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  7. Nick Li

    MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  8. Lisa C Heather

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  9. Roderick N Carter

    British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  10. Sarah Cooper

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  11. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8065-4623
  12. Jimi Wills

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  13. Nicholas M Morton

    British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  14. Ana Claudia Marques

    MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5174-8092
  15. 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.
    ORCID icon "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.

Reviewing Editor

  1. Detlef Weigel, Max Planck Institute for Developmental Biology, Germany

Version history

  1. Received: January 10, 2019
  2. Accepted: May 2, 2019
  3. Accepted Manuscript published: May 2, 2019 (version 1)
  4. Version of Record published: May 30, 2019 (version 2)
  5. 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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  1. Tamara M Sirey
  2. Kenny Roberts
  3. Wilfried Haerty
  4. Oscar Bedoya-Reina
  5. Sebastian Rogatti-Granados
  6. Jennifer Y Tan
  7. Nick Li
  8. Lisa C Heather
  9. Roderick N Carter
  10. Sarah Cooper
  11. Andrew J Finch
  12. Jimi Wills
  13. Nicholas M Morton
  14. Ana Claudia Marques
  15. Chris P Ponting
(2019)
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

Share this article

https://doi.org/10.7554/eLife.45051

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    Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.