Sustained Hypoxia Reshapes Electron Transport in the Brain and Stabilizes Complex I–Deficient Mitochondria

Acclimatization to hypoxia requires the brain to implement coordinated metabolic adjustments that preserve cellular energy homeostasis under sustained reductions in oxygen availability. This process involves fundamental changes in how mitochondria route electrons through the electron transport system (ETS). Previously, we reported that hypoxic acclimatization promotes a shift toward succinate-dependent Complex II (CII) pathways, enabling ATP production despite diminished Complex I (CI) contribution. This observation raised the possibility that hypoxia-induced mitochondrial reorganization may be inherently advantageous in disorders where CI function is impaired, including Leigh syndrome, a devastating pediatric encephalopathy frequently associated with mutations affecting CI subunits or assembly factors. To test this hypothesis, we examined how prolonged exposure to 11% O 2 reshapes mitochondrial function in the vestibular nuclei (VN) of wild-type (WT) mice and NDUFS4 knockout (KO) mice, a genetic model of Leigh syndrome characterized by early and prominent VN neurodegeneration. We evaluated mitochondrial bioenergetic function ex vivo at eight different time points within a 28-day hypoxic acclimatization period. Through high-resolution respirometry, we quantified the oxygen consumption supported by CI, CII, or both combined. We also measured Complex IV (CIV – the ultimate rate-limiting enzyme in the ETS) activity to assess modifications in terminal O 2 utilization capacity. Hypoxia produced a consistent pattern in control and diseased mice. In WT mice, CI-supported respiration progressively declined, indicating a decreasing reliance on CI as acclimatization advanced. In contrast, CII-supported respiration remained relatively preserved, and CIV activity increased markedly in both WT and KO animals. This resulted in a respiratory state defined by elevated CIV capacity and reduced upstream electron flux. Notably, WT respiration progressively converged toward the KO profile. NDUFS4 KO animals, which show a CI-restricted metabolic state in normoxia, remained stable throughout hypoxic exposure, suggesting that hypoxia imposes an operating regime that aligns closely with their intrinsic mitochondrial configuration. Taken together, these findings support the view that acclimatization to hypoxia guides brainstem mitochondria toward a functional state that minimizes CI dependence and increasingly channels respiration through CII. This hypoxia-driven convergence may stabilize energy metabolism in CI-deficient tissue and provides a compelling mechanistic framework for understanding the anatomical and functional remarkable recovery previously described in hypoxia-treated NDUFS4-deficient mice. Understanding how this acclimatized metabolic state is achieved may reveal new opportunities for therapeutic intervention in mitochondrial diseases characterized by CI dysfunction, such as Leigh syndrome, Parkinson´s disease, and Alzheimer. This abstract was presented at the American Physiology Summit 2026 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.