Research Article

Hypoxia as a therapy for mitochondrial disease

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Science  01 Apr 2016:
Vol. 352, Issue 6281, pp. 54-61
DOI: 10.1126/science.aad9642

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Thriving on a breath of low oxygen

Mitochondrial diseases are debilitating and largely untreatable. Most are caused by genetic mutations that impair the mitochondrial respiratory chain, which generates cellular energy. Because these diseases do not affect all tissues equally, it is thought that endogenous mechanisms exist that can help cells cope with mitochondrial defects. Jain et al. identified the hypoxia response, a mechanism that helps cells adapt when oxygen is limited, as a potent suppressor of mitochondrial dysfunction (see the Perspective by Shoubridge). Mouse models of the mitochondrial disease Leigh syndrome showed fewer symptoms and a dramatically extended life span when raised in a hypoxic environment.

Science, this issue p. 54; see also p. 31


Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

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