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A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells
- Source :
- Antioxidants, Volume 10, Issue 8, Antioxidants, Vol 10, Iss 1160, p 1160 (2021)
- Publication Year :
- 2021
-
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<br />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.
- Subjects :
- 0301 basic medicine
NAF-1 (CISD2)
medicine.medical_specialty
insulin secretion
Physiology
Clinical Biochemistry
Cell
RM1-950
Mitochondrion
medicine.disease_cause
Biochemistry
Article
iron hemostasis
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
medicine
oxidative stress
Molecular Biology
Hemochromatosis
chemistry.chemical_classification
Reactive oxygen species
Cell growth
Cell Biology
Glutathione
Metabolism
medicine.disease
ferroptosis
Wolfram syndrome type 2 (WFS-T2)
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Therapeutics. Pharmacology
Oxidative stress
Subjects
Details
- ISSN :
- 20763921
- Volume :
- 10
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Antioxidants (Basel, Switzerland)
- Accession number :
- edsair.doi.dedup.....d2151edda89cd2d44e1ad97567522b90