Oxygen in mitochondrial disease: can there be too much of a good thing?

Vamsi Mootha and Patrick Chinnery wrote a short letter to the editors discussing whether or not mitochondrial disease patients should be given high-flow oxygen in medical care (Mootha & Chinnery 2018). A recommended read but I wanted to add few references describing also models where mild hypoxia has been shown to have negative effects.

Indeed, a genome-wide Cas9 screen done in Mootha’s lab identified hypoxia response to be protective against oxidative phosphorylation system (OXPHOS) defects (Jain et al. 2016) and even extend the lifespan of mice lacking a OXPHOS complex I subunit Ndusf4 (Ferrari et al. 2017). They also mentioned in the text that fruit flies carrying a mutation in OXPHOS complex II (succinate dehydrogenase, SDH) are sensitive to high oxygen (Walker et al. 2006) as are the Ndusf4 knockout mice (Jain et al. 2016).

On the other hand, the mitochondrial DNA (mtDNA) mutator mouse suffers from an anemia (Ahlqvist et al. 2015) as do many POLG disease patients (Hikmat et al. 2017) so decreasing oxygen levels is unlikely to be helpful. Also in fruit flies, hypoxia worsens many of the observed phenotypes of mitochondrial mutants (Burman et al. 2014, Whelan et al. 2010).

Clearly, as Mootha and Chinnery advocate, we need more randomized trials to better understand whether some specific mitochondrial disease patients would benefit for not having high-flow oxygen given to them.

References:

Ahlqvist KJ, Leoncini S, Pecorelli A, Wortmann SB, Ahola S, Forsström S, Guerranti R, De Felice C, Smeitink J, Ciccoli L, Hämäläinen RH, Suomalainen A. MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction. Nat Commun. 2015. PMID: 25751021

Burman JL, Itsara LS, Kayser EB, Suthammarak W, Wang AM, Kaeberlein M, Sedensky MM, Morgan PG, Pallanck LJ. A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer. Dis Model Mech. 2014. PMID: 25085991

Ferrari M, Jain IH, Goldberger O, Rezoagli E, Thoonen R, Cheng KH, Sosnovik DE, Scherrer-Crosbie M, Mootha VK, Zapol WM. Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. Proc Natl Acad Sci U S A. 2017. PMID: 28483998

Hikmat O, Charalampos T, Klingenberg C, Rasmussen M, Tallaksen CME, Brodtkorb E, Fiskerstrand T, McFarland R, Rahman S, Bindoff LA. The presence of anaemia negatively influences survival in patients with POLG disease. J Inherit Metab Dis. 2017. PMID: 28865037

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. Hypoxia as a therapy for mitochondrial disease. Science. 2016. PMID: 26917594

Mootha VK, Chinnery PF. Oxygen in mitochondrial disease: can there be too much of a good thing? J Inherit Metab Dis. 2018. PMID: 29948481

Walker DW, Hájek P, Muffat J, Knoepfle D, Cornelison S, Attardi G, Benzer S. Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant. Proc Natl Acad Sci U S A. 2006. PMID: 17056719

Whelan J, Burke B, Rice A, Tong M, Kuebler D. Sensitivity to seizure-like activity in Drosophila following acute hypoxia and hypercapnia. Brain Res. 2010. PMID: 20034480