Hypoxia ameliorates brain hyperoxia and NAD+ deficiency in a murine model of Leigh syndrome

Leigh syndrome is a severe mitochondrial neurodegenerative disease with no effective treatment. In the Ndufs4(-/-) mousemodel of Leigh syndrome, continuously breathing 11% O-2 (hypoxia) prevents neurodegeneration and leads to a dramatic extension (similar to 5-fold) in lifespan. Weinvestigated the effect of hypoxia on the brainmetabolism of Ndufs4(-/-) mice by studying blood gas tensions and metabolite levels in simultaneously sampled arterial and cerebral internal jugular venous (IJV) blood. Relatively healthy Ndufs4(-/-) and wildtype (WT) mice breathing air until postnatal age similar to 38 d were compared to Ndufs4(-/-) and WT mice breathing air until similar to 38 days old followed by 4-weeks of breathing 11% O-2. Compared to WT control mice, Ndufs4(-/-) mice breathing air have reduced brainO(2) consumption as evidenced by an elevated partial pressure of O-2 in IJV blood (PijvO2) despite a normal PO2 in arterial blood, and higher lactate/pyruvate (L/P) ratios in IJV plasma revealed by metabolic profiling. In Ndufs4(-/-) mice, hypoxia treatment normalized the cerebral venous PijvO2 and L/P ratios, and decreased levels of nicotinate in IJV plasma. Brain concentrations of nicotinamide adenine dinucleotide (NAD(+)) were lower in Ndufs4(-/-) mice breathing air than in WT mice, but preserved atWT levels with hypoxia treatment. Although mild hypoxia (17% O-2) has been shown to be an ineffective therapy for Ndufs4(-/-) mice, we find thatwhen combinedwith nicotinic acid supplementation it provides a modest improvement in neurodegeneration and lifespan. Therapies targeting both brain hyperoxia and NAD(+) deficiency may hold promise for treating Leigh syndrome. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Leigh syndrome, a severe mitochondrial neurodegenerative disease, has no effective treatment yet. However, in a mouse model of Leigh syndrome, hypoxia treatment has shown promise in preventing neurodegeneration and significantly extending lifespan. Mild hypoxia alone may not be effective, but when combined with nicotinic acid supplementation, it can provide modest improvement in neurodegeneration and lifespan. Therapies targeting both brain hyperoxia and NAD(+) deficiency may hold promise for treating Leigh syndrome.