Hypoxia caused by heat stress (HS) exacerbates intestinal epithelial cell apoptosis, and mitochondrial dysfunction plays a central role in this process. Increased hypoxia-inducible factor 1α (HIF-1α) shows an obvious antiapoptotic effect under HS. Based on the relationship between HIF-1α, mitochondrial homeostasis and BNIP3, we hypothesize that HIF-1α promotes BNIP3-mediated mitophagy to protect intestinal epithelial cells from HS-induced apoptosis. The results showed that HS destroyed the physical barrier of porcine small intestinal mucosa (disorganized microvilli, disrupted tight junctions) in vivo, accompanied by mitochondrial structure damage. The ratio of LC3II/I (p < 0.001) in the duodenum, jejunum, and ileum increased in a time-dependent manner under 72 h HS, while P62 (p < 0.001) and the Bcl-2/BAX ratio (p < 0.001) decreased continuously. In vitro, proteomic sequencing of HS-treated IPEC-J2 confirmed a negative correlation between mitochondrial function and HS, indicating HS disrupted mitochondrial homeostasis. Further experiments showed that increased HIF-1α improved mitochondrial function and promoted mitophagy; the expression of HIF-1α (p < 0.001), BNIP3 (p < 0.001), p-AMPK/AMPK (p < 0.001), Parkin (p < 0.001), and LC3II/I (p < 0.001) was synchronously upregulated under HS, whereas P62 (p < 0.001) showed the opposite trend. Critically, inhibition of BNIP3 disrupted the effect of HIF-1α on mitophagy, indicating that HIF-1α promotes IPEC-J2 mitophagy through BNIP3 under HS. What was more, increased HIF-1α alleviated HS-induced cell apoptosis (p < 0.001), while inhibition of BNIP3 could block the antiapoptotic effect of HIF-1α. In conclusion, we first clarify HIF-1α alleviates HS-induced IPEC-J2 apoptosis through BNIP3-activated mitophagy, and this regulatory axis provides a molecular target for mitigating HS-induced intestinal damage in the swine industry.
Li et al. (2025) studied this question.