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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells

Author

  • Lisa M. Nicholas
  • Bérengère Valtat
  • Anya Medina Benavente
  • Lotta Andersson
  • Mia Abels
  • Ines Mollet
  • Deepak Jain
  • Lena Eliasson
  • Nils Wierup
  • Malin Fex
  • Hindrik Mulder

Summary, in English

Objective: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcription of mitochondrial-encoded genes. However, its precise role in mitochondrial metabolism in pancreatic β-cells and, consequently, in insulin secretion remains unknown. Methods: To elucidate the role of TFB2M in mitochondrial function and insulin secretion in vitro and in vivo, mice with a β-cell specific homozygous or heterozygous knockout of Tfb2m and rat clonal insulin-producing cells in which the gene was silenced were examined with an array of metabolic and functional assays. Results: There was an effect of gene dosage on Tfb2m expression and function. Loss of Tfb2m led to diabetes due to disrupted transcription of mitochondrial DNA (mtDNA) and reduced mtDNA content. The ensuing mitochondrial dysfunction activated compensatory mechanisms aiming to limit cellular dysfunction and damage of β-cells. These processes included the mitochondrial unfolded protein response, mitophagy, and autophagy. Ultimately, however, these cell-protective systems were overridden, leading to mitochondrial dysfunction and activation of mitochondrial-dependent apoptotic pathways. In this way, β-cell function and mass were reduced. Together, these perturbations resulted in impaired insulin secretion, progressive hyperglycemia, and, ultimately, development of diabetes. Conclusions: Loss of Tfb2m in pancreatic β-cells results in progressive mitochondrial dysfunction. Consequently, insulin secretion in response to metabolic stimuli is impaired and β-cell mass reduced. Our findings indicate that TFB2M plays an important functional role in pancreatic β-cells. Perturbations of its actions may lead to loss of functional β-cell mass, a hallmark of T2D.

Department/s

  • Diabetes - Molecular Metabolism
  • Neuroendocrine Cell Biology
  • Diabetes - Islet Cell Exocytosis
  • LUDC (Lund University Diabetes Centre)-lup-obsolete
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2017-07

Language

English

Pages

651-663

Publication/Series

Molecular Metabolism

Volume

6

Issue

7

Document type

Journal article

Publisher

Elsevier GmbH

Topic

  • Endocrinology and Diabetes

Keywords

  • Insulin secretion
  • Mitochondrial metabolism
  • Pancreatic β-cells

Status

Published

Research group

  • Diabetes - Molecular Metabolism
  • Neuroendocrine Cell Biology
  • Diabetes - Islet Cell Exocytosis
  • LUDC (Lund University Diabetes Centre)-lup-obsolete

ISBN/ISSN/Other

  • ISSN: 2212-8778