NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells. (April 2023)

• Record Type: Journal Article
• Authors: Guo, Jingchao; Ye, Xiaochun; Zhao, Yongxia; Huang, Deyu; Wu, Qinghua; Ihsan, Awais; Wang, Xu
• Is Part Of: Food and chemical toxicology. Volume 174(2023)
• Publication Date: 2023-04
• Subjects: T-2 toxin -- Mitochondrial biogenesis -- Nuclear respiratory factor 2α -- Reactive oxygen species -- Mitophagy -- Mitochondrial membrane potential; ΔΨm the mitochondrial membrane potentia -- β-globin Region of haemoglobin subunit β -- AR Androgen receptor -- Atg5 Autophagy-related 5 -- C. Elegans Caenorhabditis elegans -- cDNA Complementary DNA -- ChIP-Seq Chromatin immunoprecipitation sequencing -- Cyt c Mitochondrial cytochrome c -- DAPI 4', 6'-diamidino-2-phenylindole -- DCFH-DA 2', 7'-dichlorodihydrofluorescein diacetate -- DMEM Dulbecco's Modified Eagle's Medium -- DMSO Dimethyl sulfoxide -- Drp1 Dynamin-1-like protein -- E1 Ubiquitin-activating enzyme -- E2 Ubiquitin-conjugating enzyme -- ER Endoplasmic reticulum -- FBS Fetal bovine serum -- IP Immunoprecipitation -- MPTP Mitochondrial permeability transition pore -- MtDNA Mitochondrial DNA -- NADH Nicotinamide adenine dinucleotide -- Ndna the nuclear DNA -- NRF-2α Nuclear respiratory factor 2α -- Pex5 Peroxisomal biogenesis factor 5 -- ROS Reactive oxygen species; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2023.113687
• Languages: English
• ISSNs: 0278-6915

Abstract

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.