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Elife. 2017 Apr 19;6. pii: e23813. doi: 10.7554/eLife.23813.

Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.

Author information

1
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom.
2
The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
3
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
4
Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.
5
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
6
West Midlands Medical Genetics Department, Birmingham Women's Hospital, Edgbaston, Birmingham, United Kingdom.
7
Department of Endocrinology and Internal Medicine and Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
8
New Medicines, UCB Pharma, Slough, United Kingdom.
9
Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
10
Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
11
National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
12
Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
13
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
14
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom.
15
University of Maryland School of Medicine, Baltimore, United States.
16
Metabolism, Endocrinology and Diabetes (MEND) Division, Department of Internal of Medicine, Brehm Center for Diabetes, Ann Arbor, United States.
17
Department of Medical Genetics, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
18
Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Clinical Medicine, Aarhus University, Aarhus, Denmark.

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.

KEYWORDS:

MFN2; adipose tissue; cell biology; human; human biology; leptin; medicine; mitochondria; mitofusin; obesity

PMID:
28414270
PMCID:
PMC5422073
DOI:
10.7554/eLife.23813
[Indexed for MEDLINE]
Free PMC Article

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