Cited by 94Pancreatic function and diabetesMitochondrial Function and PathologyDiabetes and associated disorders

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

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Supale, Sachin, Thorel, Fabrizio, Merkwirth, Carsten, Gjinovci, Asllan, Herrera, Pedro L., Scorrano, Luca, Meda, Paolo, Langer, Thomas +1 more·2013·Diabetes

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.

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Authors
Supale, S., Thorel, F., Merkwirth, C., Gjinovci, A., Herrera, P. L., Scorrano, L., Meda, P., Langer, T., & Maechler, P.
Affiliations
  • University of Geneva (CH)
  • University of Cologne (DE)
Corresponding author
Maechler, Pierre
Venue
Diabetes
Published
2013-09-17
Volume
62
Issue
10
Pages
3488-3499
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
OpenAlex
W2146424231
Cited by
94
References
39
Citations by year
2026: 4 · 2025: 10 · 2024: 3 · 2023: 9 · 2022: 11 · 2021: 8 · 2020: 9 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 6 · 2013: 1
FWCI
7.50
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030, 135704)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK089572, P30DK020593)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
prohibitin, PHB2, pancreatic beta cells, mitochondrial dysfunction, beta-cell apoptosis, beta-cell proliferation, insulin secretion, type 2 diabetes, mitochondrial DNA copy number, respiratory chain complex IV, mitochondrial fragmentation, glucose homeostasis, islets
MeSH terms
Insulin Secretion, Prohibitins, Animals, Blood Glucose, Cell Survival, Diabetes Mellitus, Type 2, DNA, Mitochondrial, Female, Humans, Insulin, Male, Mitochondria, Repressor Proteins, Apoptosis, Gene Deletion, Mice, Knockout, Disease Progression, GTP Phosphohydrolases, Cell Proliferation, Insulin-Secreting Cells, Mice

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