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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. / Rocha, Nuno; Bulger, David A; Frontini, Andrea; Titheradge, Hannah; Gribsholt, Sigrid Bjerge; Knox, Rachel; Page, Matthew; Harris, Julie; Payne, Felicity; Adams, Claire; Sleigh, Alison; Crawford, John; Gjesing, Anette Prior; Bork-Jensen, Jette; Pedersen, Oluf; Barroso, Inês; Hansen, Torben; Cox, Helen; Reilly, Mary; Rossor, Alex; Brown, Rebecca J; Taylor, Simeon I; McHale, Duncan; Armstrong, Martin; Oral, Elif A; Saudek, Vladimir; O'Rahilly, Stephen; Maher, Eamonn R; Richelsen, Bjørn; Savage, David B; Semple, Robert K.

In: eLife, Vol. 6, e23813, 19.04.2017.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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

APA

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

Vancouver

Rocha N, Bulger DA, Frontini A, Titheradge H, Gribsholt SB, Knox R et al. Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. eLife. 2017 Apr 19;6. e23813. https://doi.org/10.7554/eLife.23813

Author

Rocha, Nuno ; Bulger, David A ; Frontini, Andrea ; Titheradge, Hannah ; Gribsholt, Sigrid Bjerge ; Knox, Rachel ; Page, Matthew ; Harris, Julie ; Payne, Felicity ; Adams, Claire ; Sleigh, Alison ; Crawford, John ; Gjesing, Anette Prior ; Bork-Jensen, Jette ; Pedersen, Oluf ; Barroso, Inês ; Hansen, Torben ; Cox, Helen ; Reilly, Mary ; Rossor, Alex ; Brown, Rebecca J ; Taylor, Simeon I ; McHale, Duncan ; Armstrong, Martin ; Oral, Elif A ; Saudek, Vladimir ; O'Rahilly, Stephen ; Maher, Eamonn R ; Richelsen, Bjørn ; Savage, David B ; Semple, Robert K. / Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. In: eLife. 2017 ; Vol. 6.

Bibtex

@article{396abb5c95f34739b0ee1413038ceded,
title = "Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression",
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 = "Journal Article",
author = "Nuno Rocha and Bulger, {David A} and Andrea Frontini and Hannah Titheradge and Gribsholt, {Sigrid Bjerge} and Rachel Knox and Matthew Page and Julie Harris and Felicity Payne and Claire Adams and Alison Sleigh and John Crawford and Gjesing, {Anette Prior} and Jette Bork-Jensen and Oluf Pedersen and In{\^e}s Barroso and Torben Hansen and Helen Cox and Mary Reilly and Alex Rossor and Brown, {Rebecca J} and Taylor, {Simeon I} and Duncan McHale and Martin Armstrong and Oral, {Elif A} and Vladimir Saudek and Stephen O'Rahilly and Maher, {Eamonn R} and Bj{\o}rn Richelsen and Savage, {David B} and Semple, {Robert K}",
year = "2017",
month = apr,
day = "19",
doi = "10.7554/eLife.23813",
language = "English",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd.",

}

RIS

TY - JOUR

T1 - Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression

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

Y1 - 2017/4/19

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

U2 - 10.7554/eLife.23813

DO - 10.7554/eLife.23813

M3 - Journal article

C2 - 28414270

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e23813

ER -

ID: 183004855