A combined drug treatment that reduces mitochondrial iron and reactive oxygen levels recovers insulin secretion in NAF-1-deficient pancreatic cells

Ola Karmi, Yang Sung Sohn, Henri Baptiste Marjault, Tal Israeli, Gil Leibowitz, Konstantinos Ioannidis, Yaakov Nahmias, Ron Mittler*, Ioav Z. Cabantchik*, Rachel Nechushtai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 se-cretion, 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 mi-tochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Addition-ally, 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.

Original languageAmerican English
Article number1160
JournalAntioxidants
Volume10
Issue number8
DOIs
StatePublished - 21 Jul 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Ferroptosis
  • Insulin secretion
  • Iron hemostasis
  • NAF-1 (CISD2)
  • Oxidative stress
  • Wolfram syndrome type 2 (WFS-T2)

Fingerprint

Dive into the research topics of 'A combined drug treatment that reduces mitochondrial iron and reactive oxygen levels recovers insulin secretion in NAF-1-deficient pancreatic cells'. Together they form a unique fingerprint.

Cite this