Mitochondrial Mechanisms of Acclimatization to Hypoxia in the Brain and its Therapeutic Potential in Leigh Syndrome

The brain relies heavily on oxygen (O 2 ) for energy production, as disturbances in O 2 metabolism underpin numerous neurological disorders that affect millions of patients worldwide. Life at high altitudes (HA), where the O 2 bioavailability is significantly reduced, forces cerebral functions to adapt through metabolic reconfiguration(1). Recent research suggests that brain mitochondria undergo significant conformational changes during acclimatization to hypoxia (Hx), rendering a specific configuration of the electron transport system that utilizes O 2 more efficiently. Notably, these changes disrupt Complex I (C-I) stability and favor Complex II (C-II) as the electron gateway(2-5). C-II activity is modulated by succinate concentration, which increases under Hx(6). Leigh Syndrome (LS) is a mitochondrial disorder commonly linked to defects in C-I. Interestingly, the pathology of LS is reversed by Hx acclimatization in mouse models, although the mechanism remains unknown(7). In this work, we test the hypothesis that Hx acclimatization triggers a mitochondrial rewiring that favors succinate metabolism, compensates for C-I defects, and restores mitochondrial bioenergetic function in the brain of a rodent model of LS. We acclimated NDUFS4KO mice (deficient in C-I activity) to Hx (11% O 2 ) for 14 days and used high-resolution respirometry to evaluate the mitochondrial O 2 consumption rates (OCR) in the vestibular nuclei (VN) of the brainstem, an area particularly affected in LS. Our preliminary results suggest that acclimation to Hx restores mitochondrial OCR in the VN to around 70% healthy levels, potentially explaining the reversal of SL symptoms in this model. Ultimately, understanding the hypoxic acclimatization of brain cells could offer significant insights and potential treatments for degenerative brain diseases that involve impaired mitochondrial respiration, such as Leigh syndrome. 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.