Zinc Mitigates the Combined Neurotoxicity of Binary Metal Mixtures Via Mitophagy and Mitochondrial Fusion

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Dec 14

PMID 39673661

Authors

Haiqing Cai

Junxiu He

Wanting Zheng

Hong Cheng

Xiaoting Ge

Yu Bao

Yue Wei

Yanfeng Zhou

Xiaolin Liang

Xing Chen

Chaoqun Liu

Fei Wang

Xiaobo Yang

Affiliations

Soon will be listed here.

Abstract

Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity.

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PMID: 39633012 DOI: 10.1038/s41594-024-01422-3.

References

Aimo L, Mackenzie G, Keenan A, Oteiza P . Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-κB and NFAT in fetal brain. J Nutr Biochem. 2010; 21(11):1069-75. PMC: 3506428. DOI: 10.1016/j.jnutbio.2009.09.003. View

Bai M, Cui Y, Sang Z, Gao S, Zhao H, Mei X . Zinc ions regulate mitochondrial quality control in neurons under oxidative stress and reduce PANoptosis in spinal cord injury models via the Lgals3-Bax pathway. Free Radic Biol Med. 2024; 221:169-180. DOI: 10.1016/j.freeradbiomed.2024.05.037. View

Bitanihirwe B, Cunningham M . Zinc: the brain's dark horse. Synapse. 2009; 63(11):1029-49. DOI: 10.1002/syn.20683. View

Cai H, Bao Y, Cheng H, Ge X, Zhang M, Feng X . Zinc homeostasis may reverse the synergistic neurotoxicity of heavy metal mixtures in Caenorhabditis elegans. Sci Total Environ. 2023; 868:161699. DOI: 10.1016/j.scitotenv.2023.161699. View

Caito S, Aschner M . Neurotoxicity of metals. Handb Clin Neurol. 2015; 131:169-89. DOI: 10.1016/B978-0-444-62627-1.00011-1. View

Cao Y, Chen Z, Hu J, Feng J, Zhu Z, Fan Y . Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes PERK Pathway. Front Cell Dev Biol. 2022; 9:769213. PMC: 8721005. DOI: 10.3389/fcell.2021.769213. View

Chen D, Ran D, Wang C, Liu Y, Ma Y, Song R . Role of mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in Cd-induced hepatic lipid accumulation in chicken embryos. Life Sci. 2021; 284:119906. DOI: 10.1016/j.lfs.2021.119906. View

Chen H, Detmer S, Ewald A, Griffin E, Fraser S, Chan D . Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003; 160(2):189-200. PMC: 2172648. DOI: 10.1083/jcb.200211046. View

Chen W, Zhao H, Li Y . Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023; 8(1):333. PMC: 10480456. DOI: 10.1038/s41392-023-01547-9. View

10.

Chen Y, Dorn 2nd G . PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013; 340(6131):471-5. PMC: 3774525. DOI: 10.1126/science.1231031. View

11.

Cheng B, Sheng J, Wang H, Wang Y, Cao H, Li X . Selenium attenuates the association of co-exposure to arsenic, cadmium, and lead with cognitive function among Chinese community-dwelling older adults. Environ Sci Pollut Res Int. 2022; 30(13):36377-36391. DOI: 10.1007/s11356-022-24783-y. View

12.

Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L . OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004; 101(45):15927-32. PMC: 528769. DOI: 10.1073/pnas.0407043101. View

13.

Dvergsten C, Fosmire G, Ollerich D, Sandstead H . Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. I. Impaired acquisition of granule cells. Brain Res. 1983; 271(2):217-26. DOI: 10.1016/0006-8993(83)90284-6. View

14.

Dvergsten C, Fosmire G, Ollerich D, Sandstead H . Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. II. Impaired maturation of Purkinje cells. Brain Res. 1984; 318(1):11-20. DOI: 10.1016/0165-3806(84)90057-9. View

15.

Dvergsten C, Johnson L, Sandstead H . Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. III. Impaired dendritic differentiation of basket and stellate cells. Brain Res. 1984; 318(1):21-6. DOI: 10.1016/0165-3806(84)90058-0. View

16.

Fang E, Hou Y, Palikaras K, Adriaanse B, Kerr J, Yang B . Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019; 22(3):401-412. PMC: 6693625. DOI: 10.1038/s41593-018-0332-9. View

17.

Firdaus F, Zafeer M, Anis E, Ahmad M, Afzal M . Ellagic acid attenuates arsenic induced neuro-inflammation and mitochondrial dysfunction associated apoptosis. Toxicol Rep. 2018; 5:411-417. PMC: 5978009. DOI: 10.1016/j.toxrep.2018.02.017. View

18.

Gao S, Hu J . Mitochondrial Fusion: The Machineries In and Out. Trends Cell Biol. 2020; 31(1):62-74. DOI: 10.1016/j.tcb.2020.09.008. View

19.

Geisler S, Holmstrom K, Skujat D, Fiesel F, Rothfuss O, Kahle P . PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010; 12(2):119-31. DOI: 10.1038/ncb2012. View

20.

Greene A, Grenier K, Aguileta M, Muise S, Farazifard R, Haque M . Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012; 13(4):378-85. PMC: 3321149. DOI: 10.1038/embor.2012.14. View