Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop

Abstract

Vitamin K2, a natural fat-soluble vitamin, is a potent neuroprotective molecule, owing to its antioxidant effect, but its mechanism has not been fully elucidated. Therefore, we stimulated SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) in a proper dose-dependent manner, followed by a treatment of vitamin K2. In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, and the accumulation of reactive oxygen species (ROS) was increased. Moreover, the treatment of 6-OHDA promoted mitochondria-mediated apoptosis and abnormal mitochondrial fission and fusion. However, vitamin K2 significantly suppressed 6-OHDA-induced changes. Vitamin K2 played a significant part in apoptosis by upregulating and downregulating Bcl-2 and Bax protein expressions, respectively, which inhibited mitochondrial depolarization, and ROS accumulation to maintain mitochondrial structure and functional stabilities. Additionally, vitamin K2 significantly inhibited the 6-OHDA-induced downregulation of the MFN1/2 level and upregulation of the DRP1 level, respectively, and this enabled cells to maintain the dynamic balance of mitochondrial fusion and fission. Furthermore, vitamin K2 treatments downregulated the expression level of p62 and upregulated the expression level of LC3A in 6-OHDA-treated cells via the PINK1/Parkin signaling pathway, thereby promoting mitophagy. Moreover, it induced mitochondrial biogenesis in 6-OHDA damaged cells by promoting the expression of PGC-1α, NRF1, and TFAM. These indicated that vitamin K2 can release mitochondrial damage, and that this effect is related to the participation of vitamin K2 in the regulation of the mitochondrial quality-control loop, through the maintenance of the mitochondrial quality-control system, and repair mitochondrial dysfunction, thereby alleviating neuronal cell death mediated by mitochondrial damage.

A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis

“…There is also evidence that VK2 supplementation reduces the diabetes development risk, as just 10 μg/day of VK2 can lower diabetes risk by 7% . In addition, numerous studies have demonstrated that VK2 possesses antioxidative and mitochondrial protective abilities. , It is inspiring that latest study reported vitamin K cycle as an effective ferroptosis suppressor . However, research studies have not well explained its potential actions between ferroptosis and T2DOP.…”

Protective Effect of Vitamin K2 (MK-7) on Acute Lung Injury Induced by Lipopolysaccharide in Mice

“…Our results showed that treatment with VK2 improved the mitochondrial function, and increased the PINK1/Parkin signaling pathway of mitophagy, the fusion protein Mfn2, and mitochondrial biogenesis regulator PGC-1α expression. Previous studies have shown that VK2 could reinstate mitophagic activities by upregulating PINK1 and Parkin proteins [ 30 , 53 ]. Furthermore, as a mitochondrial electron carrier, VK2 could rescue PINK1-deficiency-induced mitochondrial dysfunction [ 54 ].…”

“…Furthermore, as a mitochondrial electron carrier, VK2 could rescue PINK1-deficiency-induced mitochondrial dysfunction [ 54 ]. Additionally, VK2 promoted mitochondrial fusion and biogenesis by increasing the expression of Mfn2 and PGC-1α [ 30 ]. Therefore, our results suggest that mitochondrial quality control may be an important mechanism for VK2 to improve mitochondrial function in ALI.…”

“…VK2 is absorbed more readily than VK1, and among different MKs, MK-7 has the highest bioavailability [ 25 ]. In recent years, VK2 has become an important biologically active compound, due to its variety of biological functions, including anti-inflammatory [ 26 ], antioxidant stress [ 27 ], anti-apoptosis [ 28 ], and anti-autophagy [ 29 ] activities, in addition to repairing mitochondrial damage [ 30 ]. Therefore, based on the pathogenesis of ALI and the pharmacological effects of VK2 (MK-7), we hypothesized that VK2 has favorable effects on ALI.…”

The biological responses of vitamin K2: A comprehensive review

“…It has the function of protecting mitochondria when the cell has abnormally high energy requirements. When mitochondria are damaged, the cell recognizes and clears the dysfunctional mitochondria through the Pink1 protein (Vos et al, 2012 ) and/or mitochondrial quality‐control loop (Tang et al, 2022 ). It is now known that this steady‐state imbalance is related to the occurrence of Parkinson's disease (PD) (Opdebeeck et al, 2019 ).…”