Mice but not rats modulate liver mitochondrial machinery in chronic hypoxia

Abstract

Mice (FVB) permanently living at high‐altitude have increased respiratory frequencies and sustained or increased metabolic rates. On the other hand, rats permanently living at high‐altitude (SD) have impaired respiratory control, high hematocrit and hemoglobin, signs of pulmonary hypertension, and reduced metabolism; all these considered to be detrimental. This is coincident with the fact that common rats are not found in natural high‐altitude environments. At sea level, we reported that mice, but nor rats, exposed to 21 days of hypoxia (12% O2) increase their metabolic rate (O2 consumption and CO2 production), similarly to other rodent species that are considered well adapted to high‐altitude. As mitochondria is the final user of O2 in metabolism, we were interested in the role of mitochondria behind this divergence in physiological adjustments. We used saponin‐permeabilized samples of liver (most energy‐consuming organ in rodents), 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) following the SUIT‐01 protocol in the high‐resolution respirometer O2K (OROBOROS instruments). OCR was measured with substrates activating the NADH, succinate , and fatty acid pathways of the electron transport chain (ETC). We also measured the maximum capacity of ETC by uncoupling the electron transport from the oxidative phosphorylation with CCCP. The level of activation of complexes I and II was reported as the OCR for the N or S pathway correspondingly, divided by the maximum capacity (flux control ratio).Our preliminary results show that, compared to rats, mice have significantly higher ETC maximum capacities in normoxia and hypoxia. Moreover, after 21 days of hypoxia, mice showed an increase of 43% in maximum capacity in comparison to normoxic controls, while no increase in maximum capacity was evidenced in rats. In mice, we observed that complex I is transiently hyperactivated after 1 day of hypoxia and then, its activity reduces down below control levels by day 21 of hypoxia. Contrastingly, complex II activity is reduced after one day of hypoxia, getting back to control levels by day 21 of hypoxia. Furthermore, in rats, an increased activity of complex I occurred after 21 days of hypoxia. Regardless of normoxic or hypoxic exposure, rats showed higher activation levels of complex II than mice.These results show that mice, but not rats, have the ability to modulate their liver metabolic mitochondrial machinery under chronic hypoxia. The higher and adjustable maximum capacity in mice, suggest a more powerful and plastic liver mitochondrial machinery than in rats. This might explain in part their ability to keep sustained metabolic rates under hypoxic conditions.Support or Funding InformationSupported by NSERC, the Health Respiratory Network of Québec and CIHR.