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

• DOI: 10.2337/db13-0152
• Publication Date: 2013-07-18T04:26:04Z
• Authors: Sachin Supale; Fabrizio Thorel; Carsten Merkwirth; Asllan Gjinovci; Pedro L. Herrera; Luca Scorrano; Paolo Meda; Thomas Langer; Pierre Maechler
• Keywords: Blood Glucose; Male; 0301 basic medicine; Cell Survival; Apoptosis; DNA, Mitochondrial; GTP Phosphohydrolases; Mice; 03 medical and health sciences; Insulin-Secreting Cells; Insulin Secretion; Prohibitins; Animals; Humans; Insulin; ddc:576.5; info:eu-repo/classification/ddc/612; ddc:612; Cell Proliferation; Mice, Knockout; info:eu-repo/classification/ddc/576.5; Mitochondria; 3. Good health; Diabetes Mellitus, Type 2; Disease Progression; Original Article; Female; Gene Deletion

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.