Loss of Prohibitin Induces Mitochondrial Damages Altering β-Cell Function and Survival and Is Responsible for Gradual Diabetes Development

  1. Pierre Maechler1
  1. 1Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
  2. 2Department of Genetic Medicine and Development, University of Geneva Medical Centre, Geneva, Switzerland
  3. 3Institute for Genetics, University of Cologne, Cologne, Germany.
  1. Corresponding author: Pierre Maechler, pierre.maechler{at}unige.ch.

Abstract

Prohibitins are highly conserved proteins mainly implicated in the maintenance of mitochondrial function and architecture. Their dysfunctions are associated with aging, cancer, obesity, and inflammation. However, their possible role in pancreatic β-cells remains unknown. The current study documents the expression of prohibitins in human and rodent islets and their key role for β-cell function and survival. Ablation of Phb2 in mouse β-cells sequentially resulted in impairment of mitochondrial function and insulin secretion, loss of β-cells, progressive alteration of glucose homeostasis, and, ultimately, severe diabetes. Remarkably, these events progressed over a 3-week period of time after weaning. Defective insulin supply in β-Phb2−/− mice was contributed by both β-cell dysfunction and apoptosis, temporarily compensated by increased β-cell proliferation. At the molecular level, we observed that deletion of Phb2 caused mitochondrial abnormalities, including reduction of mitochondrial DNA copy number and respiratory chain complex IV levels, altered mitochondrial activity, cleavage of L-optic atrophy 1, and mitochondrial fragmentation. Overall, our data demonstrate that Phb2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of β-cells.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0152/-/DC1.

  • C.M. is currently affiliated with the Salk Institute for Biological Studies, La Jolla, California. A.G. is currently affiliated with University College London, London, U.K. L.S. is currently affiliated with the Venetian Institute of Molecular Medicine, Padova, Italy.

  • Received January 29, 2013.
  • Accepted July 4, 2013.

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  1. Diabetes vol. 62 no. 10 3488-3499
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