Preventing and Reversing Mitochondrial Leigh Syndrome with Hypoxia

ABSTRACT Leigh syndrome is the most common pediatric manifestation of mitochondrial disease and is characterized by bilaterally symmetric, necrotic lesions in the deep gray matter of the brain. More than 80 different genes – either in the nuclear DNA or mitochondrial DNA – can underlie Leigh syndrome, yet we do not have approved medicines for this lethal disease. We recently discovered that low oxygen – hypoxia – can buffer diverse forms of mitochondrial dysfunction in human cells, worm models, and mice. In fact, breathing hypoxia is able to fully prevent brain disease in the Ndufs4 KO mouse model of Leigh syndrome, and when hypoxic breathing is initiated in mice with advanced, end-stage disease, we are able to reverse neurodegeneration. We do not know the full mechanism by which breathing hypoxia is able reverse disease, whether we can identify small molecule drugs that can target these mechanisms to reverse disease, and whether hypoxia therapy this generalize to other mouse models of mitochondrial brain disease. In this application, we will apply cutting edge single cell genomics, proteomics, mtDNA editing, and mouse physiology studies to address these three challenges. We anticipate that this project could have important implications for understanding the basic biology of neurodegeneration and neuroregeneration, with important future implications for the treatment and management of patients with mitochondrial disease.