Systems Biology | Rare Diseases | Oxygen | Calcium Uniporter

A long-term goal of our laboratory is to identify strategies with which to suppress mitochondrial dysfunction. Using a genome-wide CRISPR screen we made the unexpected discovery that hypoxia – or low oxygen – can suppress mitochondrial dysfunction in a variety of cellular and animal models. Our initial paper reporting this discovery went on to show that low inhaled oxygen can suppress neurological disease in an accurate mouse model of mitochondrial Leigh syndrome due to mitochondrial complex I deficiency. We subsequently showed that in this same mouse model, hypoxia not only prevents the development of Leigh syndrome, but also can reverse neurological disease in the mouse model with advanced disease, and that the pathology in this disorder is most likely attributable to high, unused oxygen in the brains of these mice. More recently we have been able to show that yeast, worm, and mouse models of Friedreich’s ataxia – due to recessive loss of frataxin – are suppressed by low oxygen and worsened by high oxygen. In ongoing work we are deciphering the mechanism by which low oxygen alleviates pathology, and how high oxygen can exacerbate disease.


Selected Publications
arrow Hypoxia as a therapy for mitochondrial disease
Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK.
Science: 352(6281):54-61. 2017
arrow Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome
Ferrari M, Jain IH, Goldberger O, Rezoagli E, Thoonen R, Chen K, Sosnovik DE, Scherrer-Crosbie M, Mootha VK, Zapol WM.
Proceedings of the National Academy of Sciences U.S.A.: 114(21):E4241-E4250. 2017
arrow Oxygen in mitochondrial disease: can there be too much of a good thing?
Mootha VK, Chinnery PF.
Journal of Inherited Metabolic Disease: 41(5):761-763. 2018
arrow Hypoxia rescues Frataxin loss by restoring iron sulfur cluster biogenesis
Ast T, Meisel JD, Patra S, Wang H, Grange RMH, Kim SH, Calvo SE, Orefice LL, Nagashima F, Ichinose F, Zapol WM, Ruvkun G, Barondeau DP, Mootha VK.
Cell: 177(6):1507-1521. 2019
arrow Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox?
Ast T, Mootha VK.
Nature Metabolism: 1:858-860. 2019
arrow Leigh Syndrome mouse model can be rescued by interventions that normalize brain hyperoxia, but not HIF activation
Jain IH, Zazzeron L, Goldberger O, Marutani E, Wojkiewicz GR, Ast T, Wang H, Schleifer G, Stepanova A, Brepoels K, Schoonjans L, Carmeliet P, Galkin A, Ichinose F, Zapol WM, Mootha VK.
Cell Metabolism: 30(4):824-832. 2019
Genetic screen for cell fitness in high or low exygen highlights mitochondrial and lipid metabolism
Jain IH, Calvo SE, Markhard AL, Skinner OS, To TL, Ast T, Mootha VK.
Cell. 2020