α-Lipoic acid improves mitochondrial biogenesis and dynamics by enhancing antioxidant and inhibiting Wnt/Ca2+ pathway to relieve fluoride-induced hepatotoxic injury

Yanghuan Yu; Jipeng Xu; Hao Li; Jia Lv; Yaqin Zhang; Ruiyan Niu; Jundong Wang; Yangfei Zhao; Zilong Sun

doi:10.1016/j.cbi.2023.110719

α-Lipoic acid improves mitochondrial biogenesis and dynamics by enhancing antioxidant and inhibiting Wnt/Ca²⁺ pathway to relieve fluoride-induced hepatotoxic injury

Chem Biol Interact. 2023 Nov 1:385:110719. doi: 10.1016/j.cbi.2023.110719. Epub 2023 Sep 20.

Authors

Yanghuan Yu¹, Jipeng Xu¹, Hao Li¹, Jia Lv¹, Yaqin Zhang¹, Ruiyan Niu¹, Jundong Wang¹, Yangfei Zhao², Zilong Sun³

Affiliations

¹ College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China.
² College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China. Electronic address: zyf91sky@163.com.
³ College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China. Electronic address: sunzilong2000@outlook.com.

PMID: 37739047
DOI: 10.1016/j.cbi.2023.110719

Abstract

Fluoride (F), widely present in water and food, poses a serious threat to liver health, and oxidative damage and mitochondrial damage are its main causes. As a natural mitochondrial protector and antioxidant, α-lipoic acid (ALA)'s alleviating effect on fluorosis liver injury and its underlying mechanism are still unclear. Therefore, this study established a fluorosis ALA intervention mice model to explore the mechanism of mitochondrial biogenesis, mitochondrial dynamics, and Wnt/Ca²⁺ pathway in ALA attenuating fluorosis liver injury. The results showed that ALA mitigated F-induced weight loss, hepatic structural and functional damage, hepatocytes mitochondrial damage, and decreased antioxidant levels. However, ALA did not reduce F accumulation in the femur. Further mRNA and protein detection results showed that F increased the expression levels of key genes in the mitochondrial fission (Drp1, Mff, and Fis1), mitophagy (Parkin, Pink1, and Prdx3), Wnt/Ca²⁺ pathway (Wnt5a and CaMK2), and rised the number and intensity of fluorescent spots of Drp1, but decreased the expression levels of key genes in the mitochondrial biogenesis (Sirt1, Sirt3, and PGC-1α) and fusion (OPA1, Mfn2, and Mfn1), and reduced the number and intensity of fluorescent spots of PGC-1α in the liver. However, the intervention of ALA relieved the F-induced changes in the expressions of the above genes. In conclusion, ALA mitigated F-induced hepatic injury through enhancing antioxidant capacity and inhibiting Wnt/Ca²⁺ pathway to improve mitochondrial biogenesis and dynamics disturbance. This study further reveals the hepatotoxic mechanism of F and the protective mechanism of ALA, and provides a theoretical basis for ALA as a potential preventive and palliative agent for F-induced hepatotoxic injury.

Keywords: Antioxidant; Fluoride; Mitochondrial biogenesis; Mitochondrial dynamics; Wnt/Ca(2+) pathway; α-Lipoic acid.