Mitochondria and Metabolism Journal Club
Presented by Chi Fung Lee, PhD – March 2016
Hypoxia as a Therapy for Mitochondrial Disease – by Jain et al., Science 2016
Introduction: faulty respiratory chain leads to human mitochondrial diseases and is associated with many acquired human diseases. However, how mitochondrial dysfunction links to pathogenesis is not completely described.
Methods: the authors employed a CRISPR-Cas9 screening strategy to identify the genes that are responsible for the alleviation of mitochondrial disease in cell lines (moderate disease state using antimycin A; severe disease state using antimycin A + withdrawal of pyruvate).
Results: the CRISPR-Cas9 screening identified loss of VHL (an E3 ligase for HIF1a in the ubiquitin system) to be protective to mitochondrial disease. The authors showed that genetic or pharmacological activation of HIF1a is protective against respiratory chain inhibition in cell lines and a fish model. Furthermore, chronic hypoxia treatment extends lifespan in a mouse model of Leigh syndrome, Ndufs4-null mice, and alleviates the associated neurological and metabolic phenotypes.
Discussion: the authors propose that hypoxia may induce HIF signaling by limiting cellular oxygen levels and prevent oxygen toxicity, attributing to the improved phenotypes. The data suggest further consideration of the supplementation of oxygen in treating mitochondrial disease. The relationships of HIF signaling in the pathogenesis/treatment of mitochondrial disease are, however, not completely tested in this paper.