Ethan Chow

Background: Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease currently affecting an estimated 11.9 million people worldwide, and is projected to exceed 25.2 million by 2050. ¹ PD is classically described as neuronal degeneration and alpha-synuclein aggregation in the dopaminergic neurons of the substantia nigra pars compacta.² However, recent research has implicated mitochondrial dynamics in PD, with hereditary PD genes Pink1, Parkin, and LRRK2 being implicated in quality control of mitochondria.³ Finally, a recent cohort study on serum levels of Vitamin K2 (VK2) seems to suggest a role of this vitamin in the progression of PD, with affected patients having approximately half the serum levels of healthy controls, with decreases in levels associated with greater disease severity.⁴ However, the specific mechanistic role of VK2 has not been established in the context of PD, and its clinical relevance remains unknown.

Objective: In this review, we explore the potential role of vitamin K2 in the progression of Parkinson’s disease and examine its potential in slowing progression or prevention of disease.

Search Methods: Google Scholar was used with keywords “Vitamin K2”, “Ferroptosis”, “Mitophagy / Mitochondria”, “Pink1/Parkin”, “Alpha-synuclein” for studies from 2020-2025, including studies of drosophila, rodent, and cell models.

Results: A recently discovered form of cell death, ferroptosis, involving iron-dependent lipid peroxidation and subsequent cell membrane rupture, was demonstrated to occur in PD models.⁵ VK2, particularly the MK4 form, was found to rescue lipid peroxidation and prevent ferroptosis in iron-overload conditions similar to PD.^8,9 Ferroptosis reduction was shown to slow disease progression in a drosophila model of PD.⁶ MK4 was also found to upregulate Pink1/Parkin-mediated mitophagy (lysosomal degradation of poorly functioning mitochondria). This increased mitophagy resulted in increased alpha-synuclein clearance, ROS reduction, and increases in ATP production.⁷ Such mitophagy-mediated cellular clearance is not specific to PD but was also demonstrated in amyloid-beta mutated neurons and vascular endothelial cells.^10,11

Conclusions: VK2 exhibits at least two mechanisms for protecting neurons from cell death in PD. It prevents ferroptosis by rescuing lipid peroxidation, and also clears alpha-synuclein aggregates via mitophagy. Whether low VK2 is cause or consequence of PD remains to be answered; however, therapeutic benefit still seems promising in light of successful animal studies. Finally, due to the broader implications of reducing lipid peroxidation and increasing mitophagy, MK4 may hold promise in other neurodegenerative diseases / proteinopathies.

Works Cited:

1. Su D, Cui Y, He C, et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021. BMJ. 2025;388:e080952. doi:10.1136/bmj-2024-080952
2. Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson’s disease. Lancet. 2024;403(10423):293-304. doi:10.1016/S0140-6736(23)01478-2
3. Xiao B, Kuruvilla J, Tan EK. Mitophagy and reactive oxygen species interplay in Parkinson’s disease. npj Park Dis. 2022;8(1). doi:10.1038/s41531-022-00402-y
4. Yu Y, Yu X, Cheng Q, Tang L, Shen M. The association of serum vitamin K2 levels with Parkinson’s disease: from basic case-control study to big data mining analysis. 2020;12(16):16410-16419.
5. Zhang P, Chen L, Zhao Q, et al. Ferroptosis was more initial in cell death caused by iron overload and its underlying mechanism in Parkinson’s disease. Free Radic Biol Med. 2020;152(September 2019):227-234. doi:10.1016/j.freeradbiomed.2020.03.015
6. Xia Y, Wang H, Xie Z, Liu ZH, Wang HL. Inhibition of ferroptosis underlies EGCG mediated protection against Parkinson’s disease in a Drosophila model. Free Radic Biol Med. 2024;211(December 2023):63-76. doi:10.1016/j.freeradbiomed.2023.12.005
7. Tang H, Zheng Z, Wang H, Wang L, Zhao G, Wang P. Correction: Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop (Nutrients, (2022), 14, 7, (1504), 10.3390/nu14071504). Nutrients. 2023;15(16). doi:10.3390/nu15163540
8. Mishima E, Ito J, Wu Z, et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. 2022;608(7924):778-783. doi:10.1038/s41586-022-05022-3
9. Mishima E, Wahida A, Seibt T, Conrad M. Diverse biological functions of vitamin K: from coagulation to ferroptosis. Nat Metab. 2023;5(6):924-932. doi:10.1038/s42255-023-00821-y
10. Ding F, Zhang W, Liu T, et al. MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells. Drug Des Devel Ther. 2025;19:2173-2188. doi:10.2147/DDDT.S503930
11. Lin X, Wen X, Wei Z, et al. Vitamin K2 protects against Aβ42-induced neurotoxicity by activating autophagy and improving mitochondrial function in Drosophila. Neuroreport. 2021;32(6):431-437. doi:10.1097/WNR.0000000000001599