Triggering mitochondrial plasticity in the liver of rodents is key for successful acclimatization to hypoxia

Abstract

Liver is the most metabolically active organ in mice and rats, accounting for up to 50% of the body's energy expenditure. As such, this organ is highly sensitive to the reduction in O2 availability occurring in hypoxic conditions such as high-altitude. Keeping in mind that mice, but not rats, successfully colonized habitats over 2,500 masl, we showed previously that mice only increase their metabolic rates under chronic hypoxia. Accordingly, we hypothesized here that mice and rats have divergent mitochondrial and molecular features in the liver that determine an adequate energy balance in mice (not rats) during the process of acclimatization to hypoxia. To test this hypothesis, we used saponin-permeabilized samples of liver from male adult FVB mice and SD rats after exposure to hypoxia (12% O2, for 0, 1, 7 or 21 days) to measure the mitochondrial O2 consumption rate (OCR) and the activation of the N (complex I-linked), S (complex II-linked), and NS (complex I&II-linked) electron-transfer pathways in the high-resolution respirometer O2K (OROBOROS instruments). Additional experiments were performed to evaluate the activity of representative enzymes from the glycolytic (hexokinase [HK]), aerobic (pyruvate dehydrogenase [PDH]), and anaerobic (lactate dehydrogenase [LDH]) metabolic pathways by spectrometric methods. Our results show that liver mitochondria in mice increase the OCR and improve the activation of the electron-transfer pathways S (complex II-linked) and NS (complexes I&II-linked). in line, the glycolytic and aerobic metabolic enzymatic activities (HK and PDH) increased, while the anaerobic metabolism (LDH) reduced after seven-days hypoxia. On the other hand, rats were shown to be unable of altering liver mitochondrial respiration but augmented glycolytic and anaerobic metabolic activities (HK and LDH) and concomitantly reduced the aerobic metabolism (PDH). These results show that liver mitochondria of mice display plastic responses in the utilization of oxygen during the process of acclimatization to hypoxia and that these changes are supported by adjustments in the glycolytic, aerobic, and anaerobic metabolic pathways. Contrastingly, together with the inability to adjust their mitochondrial activity, rats depend heavily on anaerobic pathways (known to be less effective) to produce energy. Our results contribute to explain why mice, but not rats, are present in high-altitude environments.