Hypoxia-inducible factor-1α promotes ferroptosis by inducing ferritinophagy and promoting lactate production in yak longissimus thoracis et lumborum postmortem

Abstract

Ferroptosis has emerged as a novel, crucial regulator of meat quality in the postmortem hypoxia environment, with its role in mediating protein oxidation and cell death. However, the interaction between ferroptosis and the hypoxia response, especially the involvement of hypoxia-inducible factor-1α (HIF-1α), remains poorly studied. This study aimed to characterize whether HIF-1α influences ferroptosis, and, if so, explore the underlying mechanisms involved. The results showed that ferroptosis mediated by HIF-1α negatively impacts meat color and water holding capacity (WHC) but improving tenderness. Inhibition of HIF-1α by 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) reduced ferroptosis, as evidenced by lower lipid ROS levels, malondialdehyde (MDA), along with higher glutathione (GSH) levels compared to the control (P < 0.05). Additionally, inhibition of HIF-1α shifted iron homeostasis towards decreased uptake via downregulation of transferrin receptor 1 (TfR1) and induced export/storage via upregulation of ferroportin (FPN) and ferritin heavy chain (FTH) (P < 0.05). The relative expression of the ferritinophagy mediator nuclear receptor coactivator 4 (NCOA4), LC3-II/LC3-I ratio, and ATG were inhibited by YC-1 (P < 0.05), these findings suggest a general decrease in ferritinophagy associated with HIF-1α inhibition. YC-1-treated samples exhibited significantly diminished lactate accumulation and lactate dehydrogenase (LDH) activity compared to the control (P < 0.05). Unexpectedly, the inhibition of ferroptosis caused by YC-1 was further amplified by lactate enhancement, suggesting that lactate can exert its suppressive effects on ferroptosis independently of HIF-1α. Collectively, these findings demonstrate that HIF-1α drives ferroptosis by regulating iron metabolism, while lactate inhibits ferroptosis in a HIF-1α-independent manner. Overall, the HIF-1α mediated ferroptosis of postmortem yak muscle had a negative impact on WHC and color, while as a contributing factor of tenderness.