Lund University is celebrating 350 years. Read more on lunduniversity.lu.se

Menu

Javascript is not activated in your browser. This website needs javascript activated to work properly.

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

Author:
  • Vladimir Sharoyko
  • Mia Abels
  • Jiangming Sun
  • Lisa Nicholas
  • Ines Mollet
  • Jelena Stamenkovic
  • Isabel Göhring
  • Siri Malmgren
  • Petter Storm
  • Joao Fadista
  • Peter Spégel
  • Metodi D Metodiev
  • Nils-Göran Larsson
  • Lena Eliasson
  • Nils Wierup
  • Hindrik Mulder
Publishing year: 2014
Language: English
Pages: 5733-5749
Publication/Series: Human Molecular Genetics
Volume: 23
Issue: 21
Document type: Journal article
Publisher: Oxford University Press

Abstract english

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.

Keywords

  • Medical Genetics

Other

Published
  • Molecular Metabolism
  • Neuroendocrine Cell Biology
  • Islet cell exocytosis
  • Diabetes and Endocrinology
  • ISSN: 0964-6906
Peter Spegel
E-mail: peter [dot] spegel [at] chem [dot] lu [dot] se

Researcher

Centre for Analysis and Synthesis

1

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00