Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression
Authors
Rocha, N
Bulger, DA
Frontini, A
Titheradge, H
Gribsholt, SB
Knox, R
Page, M
Harris, Julie
Payne, F
Sleigh, Alison
Crawford, J
Gjesing, AP
Bork-Jensen, J
Pedersen, O
Hansen, T
Cox, H
Reilly, M
Rossor, A
Brown, RJ
Taylor, SI
McHale, D
Armstrong, M
Oral, EA
Saudek, V
Richelsen, B
Publication Date
2017-04-17Journal Title
eLife
ISSN
2050-084X
Publisher
eLife Sciences Publications Ltd
Volume
6
Number
e23813
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Rocha, N., Bulger, D., Frontini, A., Titheradge, H., Gribsholt, S., Knox, R., Page, M., et al. (2017). Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. eLife, 6 (e23813) https://doi.org/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.
Keywords
MFN2, adipose tissue, cell biology, human, human biology, leptin, medicine, mitochondria, mitofusin, obesity
Sponsorship
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (100574/Z/12/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.7554/eLife.23813
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266752
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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