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Drp1 Overexpression Decreases Insulin Content in Pancreatic MIN6 Cells
Uma D Kabra1,2, Noah Moruzzi3, Per-Olof Berggren3
1Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
Abstract:
Mitochondrial dynamics and bioenergetics are central to glucose-stimulated insulin secretion by pancreatic beta cells. Previously, we demonstrated that a disturbance in glucose-invoked fission impairs insulin secretion by compromising glucose catabolism. Here, we investigated whether the overexpression of mitochondrial fission regulator Drp1 in MIN6 cells can improve or rescue insulin secretion. Although Drp1 overexpression slightly improves the triggering mechanism of insulin secretion of the Drp1-knockdown cells and has no adverse effects on mitochondrial metabolism in wildtype MIN6 cells, the constitutive presence of Drp1 unexpectedly impairs insulin content, which leads to a reduction in the absolute values of secreted insulin. Coherent with previous studies in Drp1-overexpressing muscle cells, we found that the upregulation of ER stress-related genes (BiP, Chop, and Hsp60) possibly impacts insulin production in MIN6 cells. Collectively, we confirm the important role of Drp1 for the energy-coupling of insulin secretion but unravel off-targets effects by Drp1 overexpression on insulin content that warrant caution when manipulating Drp1 in disease therapy.
Insights
Overexpressing the mitochondrial fission regulator Drp1 in pancreatic beta cells improves insulin secretion triggering but unexpectedly reduces insulin content, highlighting potential therapeutic caution.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Endocrinology
Background:
- Mitochondrial dynamics are crucial for insulin secretion in pancreatic beta cells.
- Previous work showed impaired insulin secretion due to disrupted glucose-induced mitochondrial fission.
- The role of the fission regulator Drp1 in insulin secretion requires further investigation.
Purpose of the Study:
- To investigate the effect of overexpressing the mitochondrial fission regulator Drp1 on insulin secretion in MIN6 cells.
- To determine if Drp1 overexpression can rescue or improve insulin secretion.
- To explore potential off-target effects of Drp1 manipulation.
Main Methods:
- Utilized MIN6 cell lines with Drp1 manipulation (overexpression and knockdown).
- Assessed insulin secretion, glucose catabolism, and mitochondrial metabolism.
- Analyzed the expression of endoplasmic reticulum stress-related genes.
Main Results:
- Drp1 overexpression partially improved insulin secretion triggering in Drp1-knockdown cells.
- No adverse effects on mitochondrial metabolism were observed in wildtype MIN6 cells.
- Constitutive Drp1 presence unexpectedly impaired insulin content and reduced overall secreted insulin, linked to upregulated ER stress genes (BiP, Chop, Hsp60).
Conclusions:
- Drp1 plays a vital role in the energy coupling of insulin secretion.
- Drp1 overexpression has unintended negative effects on insulin content, potentially via ER stress pathways.
- Caution is advised when considering Drp1 manipulation for therapeutic strategies targeting diabetes.
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