The Gordian Knot of Oxygen and Iron

Abstract

Mitochondrial respiratory chain (RC) dysfunction has been implicated in a wide spectrum of diseases spanning from rare to common. Monogenic disorders of RC are rare but often manifest with severe encephalopathy and psychomotor regression. Defects in the production of iron-sulfur clusters, an important co-factor for RC, causes Friedreich’s Ataxia. Moreover, mitochondrial dysfunction has been implicated in virtually all age-associated diseases including Parkinson’s disease, the second most common neurodegenerative disorder in the US. Despite extensive research efforts, the precise role of RC dysfunction in the pathogenesis of these incurable diseases remains a conundrum. In the past decade, breathing chronic, normobaric hypoxia has emerged as a potent suppressor of neurological disease in pre-clinical models of mitochondrial disease, Friedreich’s Ataxia, Parkinson’s disease, and accelerated aging. The therapeutic effect of hypoxia in these diverse neurological diseases associated with RC dysfunction raises the hypothesis that un-respired oxygen that accumulates due to RC impairment may be a pathogenic driver. The goal of my thesis work is to identify downstream consequences of mitochondrial dysfunction that can be reversed by hypoxia with the hopes of better understanding the molecular underpinnings of these neurological diseases and guiding the development of safe, effective, and practical, hypoxia-inspired therapy.