Downregulation of Iron–Sulfur Cluster Biogenesis May Contribute to Hyperglycemia-Mediated Diabetic Peripheral Neuropathy in Murine Models
Lin Wu,
Fei Huang,
Zichen Sun,
Jinghua Zhang,
Siyu Xia,
Hongting Zhao,
Yutong Liu,
Lu Yang,
Yibing Ding,
Dezhi Bian,
Kuanyu Li,
Yu Sun
Affiliations
Lin Wu
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Fei Huang
Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
Zichen Sun
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Jinghua Zhang
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Siyu Xia
Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
Hongting Zhao
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Yutong Liu
State Key Laboratory of Pharmaceutical Biotechnology, Department of Vascular Surgery, Nanjing Drum Tower Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Lu Yang
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Yibing Ding
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Dezhi Bian
Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
Kuanyu Li
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
Yu Sun
Suqian Scientific Research Institute of Nanjing University Medical School, Nanjing University, Suqian 223800, China
Background: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron–sulfur clusters are essential cofactors for numerous iron–sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. Methods: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. Results: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. Conclusions: Iron–sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN.
