Complex II-linked mitochondrial respiration is upregulated during postnatal development in high-altitude grown mice.

Recently, we have shown that chronic normobaric hypoxia (12% O - 21 days) triggers mitochondrial and cell- metabolic plasticity in the retrosplenial cortex of male adult FVB mice but not in SD rats. In these animals we reported a transient upregulation of anaerobic metabolic pathways (glycolysis + lactate metabolism) followed by an attenuation in the mitochondrial respiration. These results pointed to an optimized use of oxygen at cellular level in an area of the brain responsible of processing visual information and spatial memory. Features of great importance in the biological fitness. In the current work we investigate how the residence in high altitude (La Paz - Bolivia, 3,600 m) affects the developmental profile of the mitochondrial respiratory efficiency in the retrosplenial cortex of mice and rats. We hypothesize that the mitochondrial plasticity observed in adult mice will have a process of maturation during postnatal development. This response shall be absent in rats. To do so, we measured the mitochondrial oxygen consumption rate (OCR) in saponin-permeabilized brain samples from FVB mice and SD rats born and grown in La Paz. The animals were sacrificed at postnatal ages p7, p14, p21, and adulthood (P90), and the OCR linked to the use of NADH (N pathway), FADH (S pathway), or both (NS pathway) was quantified by means of high-resolution respirometry (OROBOROS). Our results show a pattern of maturation (increase) of the mitochondrial respiration in the retrosplenial cortex along with the postnatal development (21 days+) of mice and rats. However, an upregulation of the participation of the S pathway (complex II-linked) in the mitochondrial respiration was observed during the first three weeks of age only in mice. This observation supports previous works suggesting a key role of the complex II and succinate (substrate of complex II) in the successful cellular and mitochondrial acclimatization to hypoxia. These findings contribute to further establish FVB mice and SD rats as a model to study divergent acclimatization to hypoxia.