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Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.

Sharoyko, Vladimir LU ; Abels, Mia LU ; Sun, Jiangming LU ; Nicholas, Lisa LU ; Mollet, Ines LU ; Stamenkovic, Jelena LU ; Göhring, Isabel LU ; Malmgren, Siri LU ; Storm, Petter LU and Fadista, Joao LU , et al. (2014) In Human Molecular Genetics 23(21). p.5733-5749
Abstract
We have previously identified Transcription Factor B1 Mitochondrial (TFB1M) as a Type 2 Diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D we created a β-cell specific knockout of Tfb1 m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1 m(-/-) mice exhibited retarded glucose clearance due to impaired insulin secretion. β-Tfb1 m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules, and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1 m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by... (More)
We have previously identified Transcription Factor B1 Mitochondrial (TFB1M) as a Type 2 Diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D we created a β-cell specific knockout of Tfb1 m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1 m(-/-) mice exhibited retarded glucose clearance due to impaired insulin secretion. β-Tfb1 m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules, and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1 m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine-dimethylation of 12S ribosomal RNA (rRNA). Here, we found that levels of TFB1M and mitochondrial encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1 m(-/-) islets. Furthermore, levels of reactive oxygen species in response to cellular stress were increased while induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+)-cells in the islets. Taken together, our findings demonstrate that Tfb1 m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes due to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D. (Less)
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Contribution to journal
publication status
published
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Human Molecular Genetics
volume
23
issue
21
pages
5733 - 5749
publisher
Oxford University Press
external identifiers
  • pmid:24916378
  • wos:000343203600012
  • scopus:84930792291
ISSN
0964-6906
DOI
10.1093/hmg/ddu288
language
English
LU publication?
yes
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8c6a9760-5825-4f3f-89bd-241849d36924 (old id 4528903)
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http://www.ncbi.nlm.nih.gov/pubmed/24916378?dopt=Abstract
date added to LUP
2014-07-04 17:55:14
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2017-01-08 03:25:18
@article{8c6a9760-5825-4f3f-89bd-241849d36924,
  abstract     = {We have previously identified Transcription Factor B1 Mitochondrial (TFB1M) as a Type 2 Diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D we created a β-cell specific knockout of Tfb1 m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1 m(-/-) mice exhibited retarded glucose clearance due to impaired insulin secretion. β-Tfb1 m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules, and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1 m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine-dimethylation of 12S ribosomal RNA (rRNA). Here, we found that levels of TFB1M and mitochondrial encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1 m(-/-) islets. Furthermore, levels of reactive oxygen species in response to cellular stress were increased while induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+)-cells in the islets. Taken together, our findings demonstrate that Tfb1 m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes due to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.},
  author       = {Sharoyko, Vladimir and Abels, Mia and Sun, Jiangming and Nicholas, Lisa and Mollet, Ines and Stamenkovic, Jelena and Göhring, Isabel and Malmgren, Siri and Storm, Petter and Fadista, Joao and Spégel, Peter and Metodiev, Metodi D and Larsson, Nils-Göran and Eliasson, Lena and Wierup, Nils and Mulder, Hindrik},
  issn         = {0964-6906},
  language     = {eng},
  number       = {21},
  pages        = {5733--5749},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.},
  url          = {http://dx.doi.org/10.1093/hmg/ddu288},
  volume       = {23},
  year         = {2014},
}