Formononetin Inhibits Hepatic I/R-Induced Injury Through Regulating PHB2/PINK1/Parkin Pathway

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2022 Dec 12

PMID 36506934

Authors

Zhongying Ma

Di Zhang

Jin Sun

Qi Zhang

Yi Qiao

Yixin Zhu

Jing Niu

Qian Ren

Lun Zhou

Aidong Wen

Jingwen Wang

Affiliations

Soon will be listed here.

Abstract

Formononetin (FN), an isoflavone compound mainly isolated from soy and red clover, had showed its anti-inflammation, antioxidative effects in some degenerative diseases and cholestasis. However, the role of FN in protecting ischemia/reperfusion- (I/R-) induced liver injury and the possible mechanism were unclear. In this study, effects of FN on liver injury were investigated in a rat hepatic I/R model; further, mitophagy-related proteins were measured by immunoblotting or immunofluorescence. The possible roles of PHB2 and PINK1 in regulating mitophagy by FN were verified using adeno-associated virus knockdown. The results showed that FN had protective effects against hepatic I/R injury through regulating PINK1/Parkin-regulated mitophagy. Further, we found that FN inhibited PARL expression and prevented PGAM5 cropped by increasing the expression of PHB2. The knockdown of PINK1 or PHB2 both abolished the protective effects of FN. Taken together, our findings indicated that the isoflavone compound FN promoted PHB2/PINK1/Parkin-mediated mitophagy pathway to protect liver from I/R-induced injury. These results provided novel insights into the potential prevention strategies of FN and its underlying mechanisms.

Citing Articles

Effects of Astragaloside IV and Formononetin on Oxidative Stress and Mitochondrial Biogenesis in Hepatocytes.

Tran Q, Tran G, Velic S, Xiong H, Kaur J, Moosavi Z Int J Mol Sci. 2025; 26(2).

PMID: 39859490 PMC: 11765978. DOI: 10.3390/ijms26020774.

Potential mechanisms of formononetin against inflammation and oxidative stress: a review.

Ding M, Bao Y, Liang H, Zhang X, Li B, Yang R Front Pharmacol. 2024; 15:1368765.

PMID: 38799172 PMC: 11116718. DOI: 10.3389/fphar.2024.1368765.

Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.

Tang H, Yu Q, Chen X, Zhang J, Guo D, Guo W Sci Rep. 2024; 14(1):8535.

PMID: 38609411 PMC: 11014912. DOI: 10.1038/s41598-024-58748-7.

Ubiquitination and deubiquitination in the regulation of N-methyladenosine functional molecules.

Zhao Y, Huang J, Zhao K, Li M, Wang S J Mol Med (Berl). 2024; 102(3):337-351.

PMID: 38289385 DOI: 10.1007/s00109-024-02417-9.

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.

Ji C Int J Mol Sci. 2023; 24(9).

PMID: 37175645 PMC: 10178330. DOI: 10.3390/ijms24097938.

References

Tian J, Wang X, Tian Z . Focusing on Formononetin: Recent Perspectives for its Neuroprotective Potentials. Front Pharmacol. 2022; 13:905898. PMC: 9196267. DOI: 10.3389/fphar.2022.905898. View

Huang Z, Liu Y, Huang X . Formononetin may protect aged hearts from ischemia/reperfusion damage by enhancing autophagic degradation. Mol Med Rep. 2018; 18(6):4821-4830. PMC: 6236296. DOI: 10.3892/mmr.2018.9544. View

Lu Y, Kan H, Wang Y, Wang D, Wang X, Gao J . Asiatic acid ameliorates hepatic ischemia/reperfusion injury in rats via mitochondria-targeted protective mechanism. Toxicol Appl Pharmacol. 2017; 338:214-223. DOI: 10.1016/j.taap.2017.11.023. View

Machado Dutra J, Espitia P, Andrade Batista R . Formononetin: Biological effects and uses - A review. Food Chem. 2021; 359:129975. DOI: 10.1016/j.foodchem.2021.129975. View

Zhang Y, Yang X, Wang S, Song S, Yang X . Gentiopicroside prevents alcoholic liver damage by improving mitochondrial dysfunction in the rat model. Phytother Res. 2020; 35(4):2230-2251. DOI: 10.1002/ptr.6981. View

Wu S, Yang J, Sun G, Hu J, Zhang Q, Cai J . Macrophage extracellular traps aggravate iron overload-related liver ischaemia/reperfusion injury. Br J Pharmacol. 2021; 178(18):3783-3796. DOI: 10.1111/bph.15518. View

Huang J, Chen X, Xie A . Formononetin ameliorates IL‑13‑induced inflammation and mucus formation in human nasal epithelial cells by activating the SIRT1/Nrf2 signaling pathway. Mol Med Rep. 2021; 24(6). PMC: 8503736. DOI: 10.3892/mmr.2021.12472. View

Hao Y, Miao J, Liu W, Peng L, Chen Y, Zhong Q . Formononetin protects against cisplatin‑induced acute kidney injury through activation of the PPARα/Nrf2/HO‑1/NQO1 pathway. Int J Mol Med. 2021; 47(2):511-522. PMC: 7797437. DOI: 10.3892/ijmm.2020.4805. View

Thorgersen E, Barratt-Due A, Haugaa H, Harboe M, Pischke S, Nilsson P . The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology. 2019; 70(2):725-736. PMC: 6771474. DOI: 10.1002/hep.30508. View

10.

Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries R, Kim J . PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A. 2009; 107(1):378-83. PMC: 2806779. DOI: 10.1073/pnas.0911187107. View

11.

Williams J, Ding W . Targeting Pink1-Parkin-mediated mitophagy for treating liver injury. Pharmacol Res. 2015; 102:264-9. PMC: 4684418. DOI: 10.1016/j.phrs.2015.09.020. View

12.

Zeb A, Choubey V, Gupta R, Kuum M, Safiulina D, Vaarmann A . A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy. Redox Biol. 2021; 48:102186. PMC: 8607199. DOI: 10.1016/j.redox.2021.102186. View

13.

Zheng J, Chen L, Lu T, Zhang Y, Sui X, Li Y . MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation. Cell Death Dis. 2020; 11(4):256. PMC: 7171190. DOI: 10.1038/s41419-020-2424-1. View

14.

Deevska G, Dotson 2nd P, Mitov M, Butterfield D, Nikolova-Karakashian M . Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane. Cells. 2021; 10(6). PMC: 8224046. DOI: 10.3390/cells10061278. View

15.

Ji Y, Gao Y, Chen H, Yin Y, Zhang W . Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress. Nutrients. 2019; 11(9). PMC: 6769627. DOI: 10.3390/nu11092062. View

16.

Alauddin , Chaturvedi S, Malik M, Azmi L, Shukla I, Naseem Z . Formononetin and biochanin A protects against ritonavir induced hepatotoxicity via modulation of NfκB/pAkt signaling molecules. Life Sci. 2018; 213:174-182. DOI: 10.1016/j.lfs.2018.10.023. View

17.

Burkard M, Leischner C, Lauer U, Busch C, Venturelli S, Frank J . Dietary flavonoids and modulation of natural killer cells: implications in malignant and viral diseases. J Nutr Biochem. 2017; 46:1-12. DOI: 10.1016/j.jnutbio.2017.01.006. View

18.

Jin S, Lazarou M, Wang C, Kane L, Narendra D, Youle R . Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol. 2010; 191(5):933-42. PMC: 2995166. DOI: 10.1083/jcb.201008084. View

19.

Go K, Lee S, Zendejas I, Behrns K, Kim J . Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury. Biomed Res Int. 2016; 2015:183469. PMC: 4684839. DOI: 10.1155/2015/183469. View

20.

Ghanim A, Younis N, Metwaly H . Vanillin augments liver regeneration effectively in Thioacetamide induced liver fibrosis rat model. Life Sci. 2021; 286:120036. DOI: 10.1016/j.lfs.2021.120036. View