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

Nuno Rocha; David A Bulger; Andrea Frontini; Hannah Titheradge; Sigrid Bjerge Gribsholt; Rachel Knox; Matthew Page; Julie Harris; Felicity Payne; Claire Adams; Alison Sleigh; John Crawford; Anette Prior Gjesing; Jette Bork-Jensen; Oluf Pedersen; Inês Barroso; Torben Hansen; Helen Cox; Mary Reilly; Alex Rossor; Rebecca J Brown; Simeon I Taylor; Duncan McHale; Martin Armstrong; Elif A Oral; Vladimir Saudek; Stephen O'Rahilly; Eamonn R Maher; Bjørn Richelsen; David B Savage; Robert K Semple

doi:10.7554/eLife.23813

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

Nuno Rocha, David A Bulger, Andrea Frontini, Hannah Titheradge, Sigrid Bjerge Gribsholt, Rachel Knox, Matthew Page, Julie Harris, Felicity Payne, Claire Adams, Alison Sleigh, John Crawford, Anette Prior Gjesing, Jette Bork-Jensen, Oluf Pedersen, Inês Barroso, Torben Hansen, Helen Cox, Mary Reilly, Alex RossorRebecca J Brown, Simeon I Taylor, Duncan McHale, Martin Armstrong, Elif A Oral, Vladimir Saudek, Stephen O'Rahilly, Eamonn R Maher, Bjørn Richelsen, David B Savage, Robert K Semple

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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.

Original language	English
Article number	e23813
Journal	eLife
Volume	6
Number of pages	27
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.23813
Publication status	Published - 19 Apr 2017

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Journal Article

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10.7554/eLife.23813Licence: CC0

Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expressionFinal published version, 3.64 MBLicence: CC0

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Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., Gjesing, A. P., Bork-Jensen, J., Pedersen, O., Barroso, I., Hansen, T., Cox, H., Reilly, M., ... Semple, R. K. (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

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, SI, McHale, D, Armstrong, M, Oral, EA, Saudek, V, O'Rahilly, S, Maher, ER, Richelsen, B, Savage, DB & Semple, RK 2017, 'Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression', eLife, vol. 6, e23813. https://doi.org/10.7554/eLife.23813

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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.",

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AU - Rocha, Nuno

AU - Bulger, David A

AU - Frontini, Andrea

AU - Titheradge, Hannah

AU - Gribsholt, Sigrid Bjerge

AU - Knox, Rachel

AU - Page, Matthew

AU - Harris, Julie

AU - Payne, Felicity

AU - Adams, Claire

AU - Sleigh, Alison

AU - Crawford, John

AU - Gjesing, Anette Prior

AU - Bork-Jensen, Jette

AU - Pedersen, Oluf

AU - Barroso, Inês

AU - Hansen, Torben

AU - Cox, Helen

AU - Reilly, Mary

AU - Rossor, Alex

AU - Brown, Rebecca J

AU - Taylor, Simeon I

AU - McHale, Duncan

AU - Armstrong, Martin

AU - Oral, Elif A

AU - Saudek, Vladimir

AU - O'Rahilly, Stephen

AU - Maher, Eamonn R

AU - Richelsen, Bjørn

AU - Savage, David B

AU - Semple, Robert K

PY - 2017/4/19

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N2 - 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.

AB - 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.

KW - Journal Article

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DO - 10.7554/eLife.23813

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SN - 2050-084X

VL - 6

JO - eLife

JF - eLife

M1 - e23813

ER -

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

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