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Article

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

1
The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel
2
School of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
3
Endocrinology and Metabolism Service, Hadassah Medical Center, Jerusalem 9112102, Israel
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Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel
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Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65201, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Davide Lauro
Antioxidants 2021, 10(8), 1160; https://doi.org/10.3390/antiox10081160
Received: 4 June 2021 / Revised: 14 July 2021 / Accepted: 19 July 2021 / Published: 21 July 2021
Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich’s ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin secretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mitochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients. View Full-Text
Keywords: NAF-1 (CISD2); oxidative stress; iron hemostasis; Wolfram syndrome type 2 (WFS-T2); ferroptosis; insulin secretion NAF-1 (CISD2); oxidative stress; iron hemostasis; Wolfram syndrome type 2 (WFS-T2); ferroptosis; insulin secretion
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MDPI and ACS Style

Karmi, O.; Sohn, Y.-S.; Marjault, H.-B.; Israeli, T.; Leibowitz, G.; Ioannidis, K.; Nahmias, Y.; Mittler, R.; Cabantchik, I.Z.; Nechushtai, R. A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells. Antioxidants 2021, 10, 1160. https://doi.org/10.3390/antiox10081160

AMA Style

Karmi O, Sohn Y-S, Marjault H-B, Israeli T, Leibowitz G, Ioannidis K, Nahmias Y, Mittler R, Cabantchik IZ, Nechushtai R. A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells. Antioxidants. 2021; 10(8):1160. https://doi.org/10.3390/antiox10081160

Chicago/Turabian Style

Karmi, Ola, Yang-Sung Sohn, Henri-Baptiste Marjault, Tal Israeli, Gil Leibowitz, Konstantinos Ioannidis, Yaakov Nahmias, Ron Mittler, Ioav Z. Cabantchik, and Rachel Nechushtai. 2021. "A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells" Antioxidants 10, no. 8: 1160. https://doi.org/10.3390/antiox10081160

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