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Updated: Jun 25, 2026
High-resolution Respirometry to Measure Mitochondrial Function of Intact Beta Cells in the Presence of Natural Compounds
Published on: January 23, 2018
Deletion of the mitochondrial flavoprotein apoptosis inducing factor (AIF) induces beta-cell apoptosis and impairs
Fabienne T Schulthess1, Sophie Katz, Amin Ardestani
1Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.
Background:
Apoptosis is a hallmark of beta-cell death in both type 1 and type 2 diabetes mellitus. Understanding how apoptosis contributes to beta-cell turnover may lead to strategies to prevent progression of diabetes. A key mediator of apoptosis, mitochondrial function, and cell survival is apoptosis inducing factor (AIF). In the present study, we investigated the role of AIF on beta-cell mass and survival using the Harlequin (Hq) mutant mice, which are hypomorphic for AIF.
Methodology/Principal Findings:
Immunohistochemical evaluation of pancreata from Hq mutant mice displayed much smaller islets compared to wild-type mice (WT). Analysis of beta-cell mass in these mice revealed a greater than 4-fold reduction in beta-cell mass together with an 8-fold increase in beta-cell apoptosis. Analysis of cell cycle dynamics, using BrdU pulse as a marker for cells in S-phase, did not detect significant differences in the frequency of beta-cells in S-phase. In contrast, double staining for phosphorylated Histone H3 and insulin showed a 3-fold increase in beta-cells in the G2 phase in Hq mutant mice, but no differences in M-phase compared to WT mice. This suggests that the beta-cells from Hq mutant mice are arrested in the G2 phase and are unlikely to complete the cell cycle. beta-cells from Hq mutant mice display increased sensitivity to hydrogen peroxide-induced apoptosis, which was confirmed in human islets in which AIF was depleted by siRNA. AIF deficiency had no effect on glucose stimulated insulin secretion, but the impaired effect of hydrogen peroxide on beta-cell function was potentiated.
Conclusions/Significance:
Our results indicate that AIF is essential for maintaining beta-cell mass and for oxidative stress response. A decrease in the oxidative phosphorylation capacity may counteract the development of diabetes, despite its deleterious effects on beta-cell survival.
Insights
Apoptosis inducing factor (AIF) is crucial for maintaining beta-cell mass and survival. AIF deficiency in mice leads to reduced beta-cell mass and increased apoptosis, impacting diabetes progression.
Area of Science:
- Endocrinology
- Cell Biology
- Diabetes Research
Background:
- Apoptosis is a key factor in beta-cell death in diabetes.
- Apoptosis inducing factor (AIF) regulates apoptosis, mitochondrial function, and cell survival.
- Understanding AIF's role in beta-cell turnover is vital for diabetes management.
Purpose of the Study:
- To investigate the role of AIF in regulating beta-cell mass and survival.
- To examine the impact of AIF deficiency on beta-cell apoptosis and cell cycle dynamics.
- To assess the effect of AIF on beta-cell response to oxidative stress.
Main Methods:
- Utilized Harlequin (Hq) mutant mice with reduced AIF levels.
- Performed immunohistochemical analysis of pancreatic islets.
- Analyzed beta-cell mass, apoptosis, and cell cycle progression (BrdU, pHH3).
- Assessed beta-cell apoptosis and function following hydrogen peroxide exposure in Hq mice and human islets with AIF depletion via siRNA.
Main Results:
- Hq mice exhibited significantly smaller islets and a >4-fold reduction in beta-cell mass.
- Beta-cell apoptosis increased 8-fold in Hq mice, with G2 phase cell cycle arrest.
- AIF-deficient beta-cells showed heightened sensitivity to hydrogen peroxide-induced apoptosis.
- AIF deficiency did not affect glucose-stimulated insulin secretion but potentiated hydrogen peroxide's negative impact on beta-cell function.
Conclusions:
- AIF is essential for maintaining beta-cell mass and mediating oxidative stress response.
- Reduced oxidative phosphorylation capacity, linked to AIF deficiency, may paradoxically offer some protection against diabetes development.
- Targeting AIF could be a potential strategy in managing diabetes, balancing beta-cell survival and metabolic function.
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