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.