UCSF

The ancient philosophers emphasized the virtues of balance and moderation, which resonate across cultures. This principle extends to scientific realms, notably evident in oxygen homeostasis. While insufficient or excessive oxygen levels can be detrimental, the optimal threshold remains elusive. Throughout Earth's history, oxygen levels have fluctuated significantly, prompting the questions how organisms respond to varying oxygen tensions. This thesis examines the impacts of oxygen in diverse disease settings and investigates cellular and organismal responses to aberrant oxygen levels.

First, we delve into the “optimal” oxygen level for mitochondrial disorders. Mitochondria diseases are devastating conditions without effective therapies, affecting thousands of children globally. Hypoxia emerges as a potential therapeutic avenue, previously explored in Leigh Syndrome, showcasing extended survival and mitigation of associated deficits. This study investigates hypoxia's generalizability across mitochondrial disorders, focusing on thiamine and pyruvate dehydrogenase deficiencies, highlighting its therapeutic potential beyond Leigh Syndrome. This study also reveals that for certain disease setting, the ambient oxygen level (21% oxygen) can cause toxicity and exacerbate disease, prompting a thorough investigation into the potential toxic effects of oxygen.

While excess oxygen is toxic to all known organisms, the underlying molecular mechanisms remain largely unexplored. This work delves into the effects of excess molecular oxygen, uncovering its effect on destabilizing a subset of iron-sulfur cluster (ISC)-containing proteins. This disruption hampers crucial processes such as diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings extend to a mouse model and primary human lung cells. In particular, we reveal that the ETC is the “Achilles' heel” in hyperoxia, leading to decreased mitochondrial oxygen consumption and subsequent tissue hyperoxia. This cyclic damage affects additional ISC-containing pathways. Notably, primary ETC dysfunction exacerbates lung tissue hyperoxia.

After observing the destabilizing effects of hyperoxia on ISC proteins, our subsequent step involves a systematic exploration of the influence of diverse oxygen tensions on protein turnover. We demonstrate that the lung proteome shows the most significant changes. Remarkably, extracellular matrix (ECM) proteins are stabilized in the lung under both hypoxia and hyperoxia, implying post-translational regulation in ECM remodeling. Furthermore, we identify MYBBP1A as a potential hyperoxia transcriptional regulator, specifically involved in rRNA homeostasis. Overall, our study underscores the intricate interplay between oxygen tensions and protein turnover, highlighting key mediators of oxygen-dependent signaling pathways. Our work has broad implications for disease including hyperoxia-related pathologies such as bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.

Lastly, we investigate the nexus between impaired proteostasis, varying oxygen tensions, and cardiac diseases. Leveraging human iPSC-derived cardiomyocytes, this research reveals a significant reduction in global protein turnover rates under hypoxia, particularly affecting biosynthetic and catabolic pathways. Notably, the study identifies potential targets for prolyl hydroxylases, suggesting their role in regulating responses to chronic hypoxia. This comprehensive exploration illuminates the nuanced effects of oxygen levels on proteostasis in cardiac pathology, paving the way for deeper insights into therapeutic interventions for cardiovascular diseases.

Collectively, these comprehensive investigations offer insights into the intricate interplay between oxygen tensions, cellular responses, and the pathophysiology of disease. They pave the way for interventions across diverse disease states impacted by oxygen homeostasis.