Klebsiella Pneumoniae Induces Mitochondrial and Lactation Dysfunction in Bovine Mastitis via FNIP1-Mediated FOXO3 Phosphorylation and Ubiquitination

Abstract Bovine mastitis caused by Klebsiella pneumoniae (K. pneumoniae) poses a serious threat to dairy production and milk quality, with mitochondrial dysfunction acting as a core pathological driver. As an important transcription factor regulating mitochondrial function, Forkhead box O 3 (FOXO3) plays a role in mastitis caused by K. pneumoniae infection that has not been deeply studied. This research established in vivo and in vitro mastitis models through K. pneumoniae infection. The results showed that K. pneumoniae upregulates FOXO3 mRNA but reduces its protein abundance. Mechanistically, K. pneumoniae-activated folliculin-interacting protein 1 (FNIP1) inhibits AMP-activated protein kinase (AMPK)-mediated FOXO3 phosphorylation to block its nuclear translocation, while upregulating E3 ligase mouse double minute 2 (MDM2) to promote FOXO3 ubiquitination and degradation. FOXO3 overexpression rescues mitochondrial dysfunction, restores milk synthesis and alleviates inflammation, verifying that FOXO3 activation is a promising strategy for mastitis prevention and control.