Free Fatty Acids Induce Apoptosis of Mammary Epithelial Cells of Ketotic Dairy Cows via the Mito-ROS/NLRP3 Signaling Pathway

• Published in: Journal of agricultural and food chemistry Vol. 71; no. 34; pp. 12645 - 12656
• Main Authors: Chang, Renxu, Jia, Hongdou, Dong, Zhihao, Xu, Qiushi, Liu, Lei, Majigsuren, Zolzaya, Batbaatar, Tugsjargal, Xu, Chuang, Yang, Qing, Sun, Xudong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30.08.2023
• Subjects: Agricultural and Environmental Chemistry; Animals; apoptosis; Apoptosis - drug effects; Cattle; early lactation; epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; epithelium; Fatty Acids, Nonesterified - pharmacology; Female; food chemistry; inflammasomes; Inflammasomes - metabolism; inflammation; ketosis; Ketosis - drug therapy; Ketosis - metabolism; mammary glands; Mammary Glands, Animal; milk yield; mitochondria; Mitochondria - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; oligomerization; reactive oxygen species; Signal Transduction - drug effects; NLRP3; apoptosis; bovine mammary epithelial cells; Mito-ROS
• ISSN: 0021-8561; 1520-5118; 1520-5118
• DOI: 10.1021/acs.jafc.3c02090

Early lactation increases metabolic stress in ketotic dairy cows, leading to mitochondrial damage, apoptosis, and inflammatory response in mammary epithelial cells. The pyrin domain 3 (NLRP3) pathway involving the mitochondrial reactive oxygen species (Mito-ROS)-induced nucleotide-binding oligomerization domain-like receptor has been recognized as a key mechanism in this inflammatory response and cell apoptosis. This study aimed to elucidate the underlying regulatory mechanism of Mito-ROS–NLRP3 pathway-mediated mammary epithelial cell apoptosis in dairy cows with ketosis. Mitochondrial damage and cellular apoptotic program and NLRP3 inflammasome activation were observed in the mammary gland of ketotic cows. Similar damage was detected in MAC-T cells treated with exogenous fatty acids (FFAs). However, NLRP3 inhibitor MCC950 pretreatment or Mito-ROS scavenging by MitoTEMPO attenuated apoptosis in FFA-induced MAC-T cells by inhibiting the NLRP3 inflammasome pathway. These findings reveal that the Mito-ROS–NLRP3 pathway activation is a potent mechanism underlying mammary epithelial cell apoptosis in response to metabolic stress in ketotic dairy cows, which further contributes to reduced milk yield.