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Visualization of Endogenous Mitophagy Complexes In Situ in Human Pancreatic Beta Cells Utilizing Proximity Ligation Assay
Published on: May 2, 2019
Genetic ablation of p62/SQSTM1 demonstrates little effect on pancreatic β-cell function under autophagy deficiency
Toshinaru Fukae1, Takeshi Miyatsuka2, Miwa Himuro3
1Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Abstract:
Autophagy is known to play an essential role in intracellular quality control through the degradation of damaged organelles and components. We previously demonstrated that β-cell-specific autophagy deficient mice, which lack Atg7, exhibited impaired glucose tolerance, accompanied by the accumulation of sequestosome 1/p62 (hereafter referred to as p62). Whereas p62 has been reported to play essential roles in regulating cellular homeostasis in the liver and adipose tissue, we previously showed that β-cell-specific p62 deficiency does not cause any apparent impairment in glucose metabolism. In the present study, we investigated the roles of p62 in β cells under autophagy-deficient conditions, by simultaneously inactivating both Atg7 and p62 in a β-cell specific manner. Whereas p62 accumulation was substantially reduced in the islets of Atg7 and p62 double-deficient mice, glucose tolerance and insulin secretion were comparable to Atg7 single-deficient mice. Taken together, these findings suggest that the p62 accumulation appears to have little effect on β-cell function under conditions of autophagy inhibition.
Insights
Autophagy dysfunction in beta cells impairs glucose tolerance. However, blocking p62 accumulation alongside autophagy deficiency does not further affect glucose metabolism, suggesting p62 is not critical for beta cell function under these conditions.
Area of Science:
- Cell Biology
- Metabolic Diseases
- Endocrinology
Background:
- Autophagy is crucial for cellular quality control, degrading damaged components.
- Beta-cell specific autophagy deficiency (Atg7 knockout) impairs glucose tolerance and increases p62.
- Beta-cell specific p62 deficiency alone does not affect glucose metabolism.
Purpose of the Study:
- To investigate the role of p62 in beta cells under autophagy-deficient conditions.
- To determine if p62 accumulation contributes to impaired glucose metabolism in autophagy-deficient beta cells.
Main Methods:
- Generated double-deficient mice with beta-cell specific inactivation of both Atg7 and p62.
- Assessed glucose tolerance and insulin secretion in single (Atg7) and double knockout mice.
- Quantified p62 accumulation in pancreatic islets.
Main Results:
- Simultaneous inactivation of Atg7 and p62 in beta cells substantially reduced p62 accumulation.
- Glucose tolerance and insulin secretion in double knockout mice were comparable to Atg7 single knockout mice.
- p62 accumulation did not exacerbate the glucose intolerance observed in Atg7 deficient mice.
Conclusions:
- p62 accumulation has minimal impact on beta-cell function during autophagy inhibition.
- The detrimental effects of autophagy deficiency on glucose metabolism in beta cells are not mediated by p62 accumulation.
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