NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells

Jingchao Guo; Xiaochun Ye; Yongxia Zhao; Deyu Huang; Qinghua Wu; Awais Ihsan; Xu Wang

doi:10.1016/j.fct.2023.113687

NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells

Food Chem Toxicol. 2023 Apr:174:113687. doi: 10.1016/j.fct.2023.113687. Epub 2023 Feb 28.

Authors

Jingchao Guo¹, Xiaochun Ye¹, Yongxia Zhao², Deyu Huang², Qinghua Wu³, Awais Ihsan⁴, Xu Wang⁵

Affiliations

¹ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
² MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
³ College of Life Science, Institute of Biomedicine, Yangtze University, Jingzhou, 434025, China.
⁴ Department of Biosciences, COMSATS University Islamabad, Sahiwal campus, Pakistan.
⁵ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. Electronic address: wangxu@mail.hzau.edu.cn.

PMID: 36863559
DOI: 10.1016/j.fct.2023.113687

Abstract

T-2 toxin is a natural contaminant in grain cereals produced by species of Fusarium. Studies indicate that T-2 toxin can positively affect mitochondrial function, but the underlying mechanism is unclear. In this study, we examined the role of nuclear respiratory factor 2α (NRF-2α) in T-2 toxin-activated mitochondrial biogenesis and the direct target genes of NRF-2α. Furthermore, we investigated T-2 toxin-induced autophagy and mitophagy, and the role of mitophagy in changes in mitochondrial function and apoptosis. It was found that T-2 toxin significantly increased NRF-2α levels and nuclear localization of NRF-2α was induced. NRF-2α deletion significantly increased the production of reactive oxygen species (ROS), abrogated T-2 toxin-induced increases in ATP and mitochondrial complex I activity, and inhibited the mitochondrial DNA copy number. Meanwhile, With chromatin immunoprecipitation sequencing (ChIP-Seq), various novel NRF-2α target genes were identified, such as mitochondrial iron-sulphur subunits (Ndufs 3,7) and mitochondrial transcription factors (Tfam, Tfb1m, and Tfb2m). Some target genes were also involved in mitochondrial fusion and fission (Drp1), mitochondrial translation (Yars2) and splicing (Ddx55), and mitophagy. Further studies showed that T-2 toxin induced Atg5 dependent autophagy and Atg5/PINK1-dependent mitophagy. In addition, mitophagy defects increase ROS production, inhibit ATP levels and the expression of genes related to mitochondrial dynamics, and promote apoptosis in the presence of T-2 toxins. Altogether, these results suggest that NRF-2α plays a critical role in promoting mitochondrial function and biogenesis through regulation of mitochondrial genes, and, interestingly, mitophagy caused by T-2 toxin positively affected mitochondrial function and protected cell survival against T-2 toxin.

Keywords: Mitochondrial biogenesis; Mitochondrial membrane potential; Mitophagy; Nuclear respiratory factor 2α; Reactive oxygen species; T-2 toxin.

MeSH terms

Adenosine Triphosphate / metabolism
Mitochondria / metabolism
Mitophagy
Nuclear Respiratory Factors / metabolism
Reactive Oxygen Species / metabolism
T-2 Toxin* / metabolism

Substances

Nuclear Respiratory Factors
T-2 Toxin
Reactive Oxygen Species
Adenosine Triphosphate