Living at high altitude induces a switch from complex I to complex II in hepatic mitochondria of mice during postnatal development

Abstract

Living at high altitude (HA) requires physiological and metabolic adjustments to sustain adequate homeostasis. Mitochondria play a key role in these adaptation processes as it consumes >85% of cellular O 2 to produce energy. In adults, HA hypoxia can induce structural changes in the electron transport chain (ETC) to optimize the use of O 2 . In newborn, postnatal development at HA results in slower growth rate and delayed development for some important homeostatic functions. While there is evidence that in species adapted to HA O 2 utilization is optimized, potential underlying plasticity of metabolic pathways during postnatal development is unknown. Because we already demonstrated that FVB mice are a good model to study HA adaptation, we used this laboratory strain to evaluate mitochondrial O 2 consumption rates (OCR) of liver samples during postnatal development and at adulthood at sea level (SL - Quebec, Canada) and in animals that have been raised at HA for >50 generations (La Paz, Bolivia, 3600m). Using the high-resolution oxygraph Oroboros O2k, we measured OCR in mice at postnatal day 7 (P7), 14 (P14), 21 (P21) and 60 (adults – P60) under states of maximum capacity (ET) with substrates for complex I (ET N – pyruvate, malate, glutamate), complex II (ET S – succinate), or I + II (maximal OCR - ET NS ). Our results show that ET N was considerably reduced at all ages in HA compared to SL mice (P7, -92%; P14, -86%; P21, -87%). Contrastingly, ET S was 32% higher in HA P21 mice while it was 30% lower in HA adults compared to SL. No difference was found for ET NS during postnatal development, but values were lower in HA adults compared with SL (101 ± 26 vs 167 ± 43 pmol/s*mg). We also calculated the relative contribution of CI and CII to maximal OCR (ET NS ). While CI contribution was substantially lower at all ages in HA mice compared to SL, CII participation was higher at P7 (+41%), P14 (+14%) and P21 (+16%) but was unchanged at adulthood. These results suggest that at HA, a development shift occurs from CI to CII, allowing maximal OCR (ET NS ) to remain unchanged between HA and SL. This shift might be a protective mechanism since the activity of CII is only dependent on the availability of its substrate (succinate), while CI is more sensitive to decreases in intracellular O 2 . This reprogramming was absent in adults; both CI and CII activity decreased at HA compared to SL. These differences highlight the distinct effect of HA hypoxia at different life stages. Funded by NSERC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.