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.
journal_name
Elifejournal_title
eLifeauthors
Rocha N,Bulger DA,Frontini A,Titheradge H,Gribsholt SB,Knox R,Page M,Harris J,Payne F,Adams C,Sleigh A,Crawford J,Gjesing AP,Bork-Jensen J,Pedersen O,Barroso I,Hansen T,Cox H,Reilly M,Rossor A,Brown RJ,Taylor SIdoi
10.7554/eLife.23813subject
Has Abstractpub_date
2017-04-19 00:00:00issn
2050-084Xjournal_volume
6pub_type
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