A Translatable Form of Hypoxia Therapy for Impaired Mitochondrial Proteostasis

PROJECT ABSTRACT Our previous work demonstrated that hypoxic breathing, simulating high-altitude living, can prevent and reverse neurological damage in a mouse model of mitochondrial electron transport chain (ETC) deficiency caused by mutations in a key complex 1 subunit. This research revealed that chronic hypoxia significantly extends lifespan

and rescues biomarkers, behavior, and neuropathology. Building on these findings, a Phase 1 clinical trial exposing healthy volunteers to controlled hypoxia was performed. To expand the understanding of hypoxia therapy's broader applicability, we are now testing the ability of low oxygen to rescue additional mitochondrial diseases caused by mutations in the mitochondrial proteostasis

system. Furthermore, we propose investigating two potential mechanisms of hypoxia-mediated rescue: (1) activation of the hypoxia-inducible factor (HIF) transcriptional response to promote metabolic adaptations and (2) stabilization of iron-sulfur (Fe-S) cluster-containing protein complexes affected by ETC dysfunction.

By elucidating these mechanisms, this research will provide critical insights into optimizing hypoxia-based therapies for mitochondrial diseases and inform treatment strategies for broader clinical applications.