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ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis

Abstract

Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1−/−) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1−/− mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1−/−, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1−/− β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.

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Fig. 1: Effects of IF1 on insulin release in islets from mice.
Fig. 2: Effects of IF1 on β-cell mass in pancreas from mice.
Fig. 3: β-cell ultrastructural changes assessed by transmission EM on isolated islets from mice.
Fig. 4: IF1 OE and knockdown in INS-1 cells.
Fig. 5: Effects of IF1 on mitochondrial oxidative phosphorylation.
Fig. 6: Effects of IF1 on ATP content and glycolysis flux in cultured INS-1 cells.
Fig. 7: IF1 influences mitochondrial membrane potential and ROS level in cultured INS-1 cells.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by a Basic Science Award (#1-17-IBS-184) from the American Diabetes Association to Q.Y., an NIH (R01HL135336) and a Grant-in-aid (#14GRNT20490216) from American Heart Association to Q.Y., and a Post-doctoral Fellowship (13POST14180006) from American Heart Association and the National Natural Science Foundation of China (81500312) to Q.L.

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Q.Y. and Q.L. proposed study concept, investigation design, methodology, and data interpretation; K.Z., R.B., Q.L., and Q.Y. wrote the paper; K.Z., R.B., F.H., K.Y., and Y.D. conducted experiments and statistical analysis; L.L. and M.Y. provided technical and material support. All authors read and approved the final paper.

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Correspondence to Qinqiang Long or Qinglin Yang.

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Zhang, K., Bao, R., Huang, F. et al. ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00670-x

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