2024: GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment

[pfpcnews]

NOTE: Thyroid hormones (T3) regulates the expression of GPX4 (Glutathione Peroxidase 4). T3 can upregulate GPX4 expression, thus enhancing cellular antioxidant defenses. Decreased GPX4 activity has been linked to increased susceptibility to ferroptosis, a form of regulated cell death involving lipid peroxidation.

Zhao P, Yuan Q, Liang C, Ma Y, Zhu X, Hao X, Li X, Shi J, Fu Q, Fan H, Wang D - "GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy" Sci Total Environ 927:172069. doi: 10.1016/j.scitotenv.2024.172069
https://www.sciencedirect.com/science/a ... 9724022125

Highlights

•Fluoride exposure triggers hippocampal neuronal ferroptosis.

•Fluoride exposure facilitates GPX4 degradation via enhancing chaperone-mediated autophagy (CMA) activity.

•MtROS accumulation under fluoride stress contributes to CMA of GPX4 and neuronal ferroptosis.

•Fer-1 or NAC rescues fluoride-evoked hippocampal neuronal injury and cognitive deficits.

Abstract

Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment.

SEE also:

(Sevoflurane)

Liu H, Yan L, Niu H, Miao Z - "Effects of Glutathione Tablets on Ferroptosis Pathway and Oxidative Stress-Related Indexes in Serum of Patients Undergoing Sevoflurane Inhalation General Anesthesia and Its Clinical Significance" Altern Ther Health Med AT9641 (2023).
http://alternative-therapies.com/oa/index.html?fid=9641

Abstract

Objective: To explore the effect of glutathione on serum oxidative stress, inflammatory reaction, and brain injury in patients with Sevoflurane inhalation general anesthesia based on iron metabolism pathway.

Methods: From January 2018 to January 2023, 120 patients undergoing Sevoflurane inhalation anesthesia in Xingtai Third Hospital were divided into a control group and an observation group. The control group was given routine treatment, and the observation group patients were given oral glutathione tablets 2 weeks before anesthesia based on the control group. Relevant basic data of patients were collected 3 days before operation (T0), 1 day after the operation (T1), 3 days (T2), and 7 days (T3) respectively, and the serum oxidative stress indicators of patients in each group were measured by ELISA: SOD, MDA, GSH, Hif-1α, ferroptosis related indicators: SIRT3, GPX4; related inflammatory indicators: IL-1β, TGF-β, IL-33; neuronal injury related proteins: MBP, NGF, and statistical analysis of the data.

Results: There was no significant difference in general conditions and operation time between the two groups (P > .05). Compared with the control group, the observation group showed significant differences in oxidative stress indicators: SOD in the observation group at T1, SOD, and Hif-1α in the observation group at T2, and SOD, MDA, GSH and Hif-1α in the observation group at T3. 1α, there were significant differences compared with the indicators of the control group at the same time (P < .001). In terms of inflammatory factor indicators, compared with the control group, there were significant differences in IL-1β at T1, TGF-β, and IL-33 at T2, and IL-1β, TGF-β and IL-33 at T3. (P < .001). In terms of ferroptosis indicators, compared with the control group, there were significant differences in SIRT3 at T1, SIRT3, and GPX4 at T2, and SIRT3 and GPX4 at T3 (P < .001). In terms of nerve injury-related proteins, in patients, MBP levels were negatively correlated with SIRT3 (r=-0.8979, P < .0001), MBP levels were positively correlated with GPX4 (r=0.528, P < .0001), and NGF levels were positively correlated with SIRT3 (r=0.8979, P < .0001), NGF level was negatively correlated with GPX4 (r=0.528, P < .0001).

Conclusion: Glutathione tablets can alleviate sevoflurane-induced ferroptosis and oxidative stress by elevating GPX4 protein levels, and glutathione tablets have an ameliorative effect on brain injury in patients with sevoflurane inhalation anesthesia.

[admin]

Thanks Brad, here are more studies on fluoride-induced ferroptosis:

Geng N, Dong S, Xie P, Zhang Y, Shi R, Chen C, Xu Z, Chen Q - "Excessive fluoride induces ovarian function impairment by regulating levels of ferroptosis in fluorosis women and ovarian granulosa cells" Reprod Toxicol 125:108556 (2024). doi: 10.1016/j.reprotox.2024.108556
https://linkinghub.elsevier.com/retriev ... 24)00023-6
"It is concluded therefore that NaF increases the expression of p53 and inhibits ovarian granulosa cell ferroptosis preventive protein expression, resulting in abnormal hormone secretion and the ovarian dysfunction."

Wang D, Yin K, Zhang Y, Lu H, Hou L, Zhao H, Xing M - "Novel pathways of fluoride-induced hepatotoxicity: P53-dependent ferroptosis induced by the SIRT1/FOXOs pathway and Nrf2/HO-1 pathway" Comp Biochem Physiol C Toxicol Pharmacol 264:109526 (2022). doi: 10.1016/j.cbpc.2022.109526.
https://pubmed.ncbi.nlm.nih.gov/36455829/

See also: studies on SIRT

Wang D, Yin K, Zhang Y, Lu H, Hou L, Zhao H, Xing M - "Fluoride induces neutrophil extracellular traps and aggravates brain inflammation by disrupting neutrophil calcium homeostasis and causing ferroptosis" Environ Pollut 331(Pt 1):121847 (2023) doi: 10.1016/j.envpol.2023.121847. Epub ahead of print.
https://www.sciencedirect.com/science/a ... 9123008497

• "In the past, the vast majority of the world’s population consumed iodized salt to reduce iodine deficiency disorders, leaving most of the population in a state of iodine excess [118,119]."
  in: Ji F, Qiu X - "Non-Apoptotic Programmed Cell Death in Thyroid Diseases" Pharmaceuticals (Basel) 15(12):1565. doi: 10.3390/ph15121565
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788139/
  
  Marino F, Guasti L, Cosentino M, De Piazza D, Simoni C, Bianchi V, Piantanida E, Saporiti F, Cimpanelli MG, Crespi C, Vanoli P, De Palma D, Klersy C, Frigo GM, Bartalena L, Venco A, Lecchini S - "Thyroid hormone and thyrotropin regulate intracellular free calcium concentrations in human polymorphonuclear leukocytes: in vivo and in vitro studies" Int J Immunopathol Pharmacol 19(1):149-60 (2006)
  https://link.springer.com/article/10.10 ... 22-03401-5

Wu Y, Zhang X, Chen J, Cao J, Feng C, Luo Y, Lin Y - "Self-recovery study of fluoride-induced ferroptosis in the liver of zebrafish (Danio rerio)" Aquat Toxicol 251:106275 (2022) doi: 10.1016/j.aquatox.2022.106275
https://www.sciencedirect.com/science/a ... 5X22002016