Formaldehyde (FA) causes neurotoxicity and contributes to the occurrence of neurodegenerative diseases. However, the mechanism of FA-induced neurotoxicity has not been fully elucidated. Ferritinophagy, an autophagy process of ferritin mediated by the nuclear receptor coactivator 4 (NCOA4), is a potential mechanism of neurotoxicity. In this study, we explored whether ferritinophagy is associated with the neurotoxicity of FA. Our results showed that FA (50, 100, 200 μM; 24 h) exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, which was evidenced by the upregulated autophagic flux, the increased colocalizations of NCOA4 with ferritin heavy chain (FTH1) and NCOA4 with microtubule-associated protein 1 light chain-3B (LC3B), the augmented expression of NCOA4, and the reduced content of FTH1. We also found that FA (0.1, 1, and 10 μmol, i.c.v., 7d) administration boosted ferritinophagy in the hippocampus of Sprague-Dawley (SD) rats, which was demonstrated by the accumulated autophagosomes, the increased expressions of LC3II/I and NCOA4, and the decreased contents of p62 and FTH1 in the hippocampus. Further, we confirmed that inhibition of ferritinophagy by silencing the expression of NCOA4 decreased FA-induced toxic damage in HT22 cells. These results indicated that FA induces neurotoxicity by promoting ferritinophagy. Our findings suggest a potential mechanism insight into the FA-induced neurotoxicity, which in turn provides a new thought for the treatment of FA-related neurodegenerative diseases.
BarthSGlickDMacleodKF (2010) Autophagy: assays and artifacts. The Journal of Pathology221(2): 117–124.
2.
ChangXWangXLiJ, et al. (2021) Silver nanoparticles induced cytotoxicity in HT22 cells through autophagy and apoptosis via PI3K/AKT/mTOR signaling pathway. Ecotoxicology and Environmental Safety208: 111696.
3.
ChenJWangHLuoC, et al. (2020) Chd8 rescued TBI-induced neurological deficits by suppressing apoptosis and autophagy via wnt signaling pathway. Cellular and Molecular Neurobiology40(7): 1165–1184.
4.
ChenKMaleyJYuPH (2006) Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis. Journal of Neurochemistry99(5): 1413–1424.
5.
ChimehUZimmermanMAGilyazovaN, et al. (2018) B355252, A novel small molecule, confers neuroprotection against cobalt chloride toxicity in mouse hippocampal cells through altering mitochondrial dynamics and limiting autophagy induction. International Journal of Medical Sciences15(12): 1384–1396.
6.
DongWTanYQinQ, et al. (2019) Polybrominated diphenyl ethers quinone induces NCOA4-mediated ferritinophagy through selectively autophagic degradation of ferritin. Chemical Research in Toxicology32(12): 2509–2516.
7.
DowdleWENyfelerBNagelJ, et al. (2014) Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nature Cell Biology16(11): 1069–1079.
8.
DuongASteinmausCMcHaleCM, et al. (2011) Reproductive and developmental toxicity of formaldehyde: a systematic review. Mutation Research728(3): 118–138.
9.
FeiXZhangYMeiY, et al. (2020) Degradation of FA reduces Abeta neurotoxicity and Alzheimer-related phenotypes. Molecular Psychiatry14: 121. 10.1038/s41380-020-00929-7.
10.
GurelACoskunOArmutcuF, et al. (2005) Vitamin E against oxidative damage caused by formaldehyde in frontal cortex and hippocampus: biochemical and histological studies. Journal of Chemical Neuroanatomy29(3): 173–178.
11.
HanSPZhouDXLinP, et al. (2015) Formaldehyde exposure induces autophagy in testicular tissues of adult male rats. Environmental Toxicology30(3): 323–331.
12.
HouWXieYSongX, et al. (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy12(8): 1425–1428.
13.
InciMZararsizIDavarciM, et al. (2013) Toxic effects of formaldehyde on the urinary system. Turkish Journal of Urology39(1): 48–52.
14.
ItoJOmiyaSRusuMC, et al. (2021) Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice. Elife10: 234.
15.
KimHChoiJRyuJ, et al. (2009) Activation of autophagy during glutamate-induced HT22 cell death. Biochemical and Biophysical Research Communications388(2): 339–344.
16.
LiXNYangSQLiM, et al. (2021) Formaldehyde induces ferroptosis in hippocampal neuronal cells by upregulation of the Warburg effect. Toxicology448: 152650.
17.
LimHNHawkinsJRHughesIA (2001) Genetic evidence to exclude the androgen receptor co-factor, ARA70 (NCOA4) as a candidate gene for the causation of undermasculinised genitalia. Clinical Genetics59(4): 284–286.
18.
LiuQPZhouDXLvMQ, et al. (2018a) Formaldehyde inhalation triggers autophagy in rat lung tissues. Toxicology and Industrial Health13: 157. 10.1177/0748233718796347.
19.
LiuXZhangYWuR, et al. (2018b) Acute formaldehyde exposure induced early Alzheimer-like changes in mouse brain. Toxicology Mechanisms and Methods28(2): 95–104.
20.
LuJMiaoJSuT, et al. (2013) Formaldehyde induces hyperphosphorylation and polymerization of Tau protein both in vitro and in vivo. Biochimica et Biophysica Acta1830(8): 4102–4116.
21.
LuZLiCMQiaoY, et al. (2008) Effect of inhaled formaldehyde on learning and memory of mice. Indoor Air18(2): 77–83.
22.
ManciasJDWangXGygiSP, et al. (2014) Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature509(7498): 105–109.
23.
ParzychKRKlionskyDJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxidants & Redox Signaling20(3): 460–473.
24.
QinXZhangJWangB, et al. (2021) Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells. Autophagy: 1–20. Epub ahead of print 2021/04/13. DOI: 10.1080/15548627.2021.1911016.
25.
SayyarZYazdinezhadAHassanM, et al. (2018) Protective effect of matricaria chamomilla ethanolic extract on hippocampal neuron damage in rats exposed to formaldehyde. Oxidative Medicine and Cellular Longevity2018: 6414317.
26.
SongurAOzenOASarsilmazM (2010) The toxic effects of formaldehyde on the nervous system. Reviews of Environmental Contamination and Toxicology203: 105–118.
27.
TangXQZhuangYYZhangP, et al. (2013) Formaldehyde impairs learning and memory involving the disturbance of hydrogen sulfide generation in the hippocampus of rats. Journal of Molecular Neuroscience49(1): 140–149.
28.
TongZHanCLuoW, et al. (2013) Accumulated hippocampal formaldehyde induces age-dependent memory decline. Age (Dordr)35(3): 583–596.
29.
TongZHanCQiangM, et al. (2015) Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer's disease. Neurobiology of Aging36(1): 100–110.
30.
TulpuleKDringenR (2013) Formaldehyde in brain: an overlooked player in neurodegeneration?Journal of Neurochemistry127(1): 7–21.
31.
WangFChenDWuP, et al. (2019) Formaldehyde, epigenetics, and Alzheimer's disease. Chemical Research in Toxicology32(5): 820–830.
32.
XiaoJZhangSTuB, et al. (2021) Arsenite induces ferroptosis in the neuronal cells via activation of ferritinophagy. Food and Chemical Toxicology151: 112114.
33.
YuLChenYToozeSA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy14(2): 207–215.
34.
ZararsizIKusIOgeturkM, et al. (2007) Melatonin prevents formaldehyde-induced neurotoxicity in prefrontal cortex of rats: an immunohistochemical and biochemical study. Cell Biochemistry and Function25(4): 413–418.
35.
ZhaiRRizakJZhengN, et al. (2018) Alzheimer's disease-like pathologies and cognitive impairments induced by formaldehyde in non-human primates. Current Alzheimer Research15(14): 1304–1321.
36.
ZhangLFreemanLENakamuraJ, et al. (2010) Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment. Environmental and Molecular Mutagenesis51(3): 181–191.
