Oxygen availability is a key determinant of cellular homeostasis, and the mitochondrial response to hypoxia is essential for maintaining energy balance and limiting oxidative stress. The hypoxia-inducible factor (HIF) orchestrates transcriptional programs that adjust mitochondrial function by reducing respiration and electron transport to limit reactive oxygen species (ROS) production. We previously reported that mice exhibit greater tolerance to hypoxia than rats, showing HIF-1 stabilization associated with decrease metabolic response under acute hypoxia, and a mitochondrial shift from complex I- to complex II-supported respiration in the brain at high altitude. Here, we investigated the role of HIF in regulating mitochondrial oxygen consumption rates (OCR) in the cerebral cortex and liver of mice and rats exposed to acute hypoxia (10 % O₂, 6 h). To determine whether these effects were HIF-dependent, a group of animals were also treated with deferoxamine (a HIF stabilizer) under normoxia or with 2-methoxyestradiol (a HIF inhibitor) under hypoxia. We demonstrated that acute hypoxia significantly decreases OCR in the liver of mice, an effect that was partially reproduced by HIF stabilization and partly prevented by HIF inhibition, indicating a HIF-dependent mitochondrial response. In contrast, OCR remained unchanged in the cerebral cortex of mice and in both tissues of rats, indicating species- and tissue-specific regulation. These findings reveal that HIF activation under acute hypoxia selectively modulates liver mitochondrial function in mice but not in rats, supporting the view that interspecific differences in HIF-mediated metabolic regulation contribute to the superior hypoxic tolerance of mice.
Maud et al. (Fri,) studied this question.