1. Cell Biology
  2. Human Biology and Medicine
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Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression

  1. Nuno M Rocha
  2. David A Bulger
  3. Andrea Frontini
  4. Hannah Titheradge
  5. Sigrid Bjerge Gribsholt
  6. Rachel Knox
  7. Matthew Page
  8. Julie Harris
  9. Felicity Payne
  10. Claire Adams
  11. Alison Sleigh
  12. John Crawford
  13. Anette Prior Gjesing
  14. Jette Bork-Jensen
  15. Oluf Pedersen
  16. Inês Barroso
  17. Torben Hansen
  18. Helen Cox
  19. Mary Reilly
  20. Alex Rossor
  21. Rebecca J Brown
  22. Simeon I Taylor
  23. Duncan McHale
  24. Martin Armstrong
  25. Elif A Oral
  26. Vladimir Saudek
  27. Stephen I O'Rahilly
  28. Eamonn R Maher  Is a corresponding author
  29. Bjørn Richelsen  Is a corresponding author
  30. David B Savage  Is a corresponding author
  31. Robert K Semple  Is a corresponding author
  1. The University of Cambridge Metabolic Research Laboratories, United Kingdom
  2. University of Pavia, Italy
  3. University of Birmingham, United Kingdom
  4. Aarhus University Hospital, Denmark
  5. UCB Pharma, United Kingdom
  6. Wellcome Trust Sanger Institute, United Kingdom
  7. University of Cambridge School of Clinical Medicine, United Kingdom
  8. Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  9. University of Copenhagen, Denmark
  10. Birmingham Women's Hospital, United Kingdom
  11. UCL Institute of Neurology, United Kingdom
  12. National Institutes of Health, United States
  13. University of Maryland School of Medicine, United States
  14. Brehm Center for Diabetes, United States
  15. The National Institute for Health Research Cambridge Biomedical Research Centre, United Kingdom
  16. Aarhus University, Denmark
Research Article
  • Cited 13
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Cite this article as: eLife 2017;6:e23813 doi: 10.7554/eLife.23813

Abstract

MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.

Article and author information

Author details

  1. Nuno M Rocha

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. David A Bulger

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Andrea Frontini

    Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
    Competing interests
    No competing interests declared.
  4. Hannah Titheradge

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    No competing interests declared.
  5. Sigrid Bjerge Gribsholt

    Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
    Competing interests
    No competing interests declared.
  6. Rachel Knox

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  7. Matthew Page

    New Medicines, UCB Pharma, Slough, United Kingdom
    Competing interests
    No competing interests declared.
  8. Julie Harris

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  9. Felicity Payne

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  10. Claire Adams

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  11. Alison Sleigh

    Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  12. John Crawford

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  13. Anette Prior Gjesing

    The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  14. Jette Bork-Jensen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  15. Oluf Pedersen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  16. Inês Barroso

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5800-4520
  17. Torben Hansen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  18. Helen Cox

    West Midlands Medical Genetics Department, Birmingham Women's Hospital, Birmingham, United Kingdom
    Competing interests
    No competing interests declared.
  19. Mary Reilly

    MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom
    Competing interests
    No competing interests declared.
  20. Alex Rossor

    MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom
    Competing interests
    No competing interests declared.
  21. Rebecca J Brown

    National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  22. Simeon I Taylor

    University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  23. Duncan McHale

    New Medicines, UCB Pharma, Slough, United Kingdom
    Competing interests
    No competing interests declared.
  24. Martin Armstrong

    New Medicines, UCB Pharma, Slough, United Kingdom
    Competing interests
    No competing interests declared.
  25. Elif A Oral

    Metabolism, Endocrinology and Diabetes Division, Department of Internal of Medicine, Brehm Center for Diabetes, Ann Arbor, United States
    Competing interests
    Elif A Oral, EAO receives grant and consulant fees from Aegerion Pharmaceuticals, and Akcea Therapeutics, scientific advisory board member for AstraZeneca, nonmaterial support from Aegerion Pharmaceuticals and Boehringer Ingelheim. None of these are pertinent for the work here..
  26. Vladimir Saudek

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  27. Stephen I O'Rahilly

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  28. Eamonn R Maher

    The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
    For correspondence
    erm1000@medschl.cam.ac.uk
    Competing interests
    No competing interests declared.
  29. Bjørn Richelsen

    Department of Endocrinology and Internal Medicine, Aarhus University, Aarhus, Denmark
    For correspondence
    bjoern.richelsen@aarhus.rm.dk
    Competing interests
    No competing interests declared.
  30. David B Savage

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    For correspondence
    dbs23@medschl.cam.ac.uk
    Competing interests
    No competing interests declared.
  31. Robert K Semple

    Wellcome Trust-MRC Institute of Metabolic Science, The University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
    For correspondence
    rks16@cam.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6539-3069

Funding

Medical Research Council (MRC_MC_UU_12012/5)

  • Nuno M Rocha

Wellcome (Wellcome Trust Postdoctoral Fellowship for Clinicians (10043/Z/15/Z))

  • Alex Rossor

National Institute for Health Research (NIHR Clinical Research Facilities for Experimental Medicine Award to Cambridge NIHR/Wellcome Trust)

  • Alison Sleigh

National Institute for Health Research (Cambridge BRC and Clinical Research Facility; Rare Disease Translational Research Collaboration)

  • Stephen I O'Rahilly
  • Eamonn R Maher
  • David B Savage
  • Robert K Semple

National Institutes of Health (Oxford-Cambridge Scholars Programme)

  • David A Bulger

Wellcome (WT098051)

  • Felicity Payne
  • Inês Barroso

National Institute of Diabetes and Digestive and Kidney Diseases (Intramural research program)

  • Elif A Oral

National Institute of Diabetes and Digestive and Kidney Diseases (RO1-DK 08811)

  • Elif A Oral

UCB Pharma (Gen 001)

  • Hannah Titheradge
  • Duncan McHale
  • Eamonn R Maher

Medical Research Council (MRC Centre grant (G0601943))

  • Mary Reilly

National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712)

  • Mary Reilly

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Written informed consent was obtained from all participants or their parents if under 18 years old for the research described and for publication of results. The research was approved by the Cambridgeshire South Research Ethics Committee, Reference no. 12/EE/0405

Reviewing Editor

  1. Ruth Loos, The Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: December 1, 2016
  2. Accepted: April 11, 2017
  3. Accepted Manuscript published: April 17, 2017 (version 1)
  4. Accepted Manuscript updated: April 19, 2017 (version 2)
  5. Version of Record published: May 8, 2017 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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