Hypoxia Ameliorates Brain Hyperoxia and NAD+ Deficiency in a Murine Model of Leigh Syndrome

Document Type

Article

Publication Date

3-11-2021

Publication Title

Molecular Genetics and Metabolism

Volume

133

Issue

1

First page number:

83

Last page number:

93

Abstract

Leigh syndrome is a severe mitochondrial neurodegenerative disease with no effective treatment. In the Ndufs4 mouse model of Leigh syndrome, continuously breathing 11% O (hypoxia) prevents neurodegeneration and leads to a dramatic extension (~5-fold) in lifespan. We investigated the effect of hypoxia on the brain metabolism 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 ~38 d were compared to Ndufs4 and WT mice breathing air until ~38 days old followed by 4-weeks of breathing 11% O . Compared to WT control mice, Ndufs4 mice breathing air have reduced brain O consumption as evidenced by an elevated partial pressure of O in IJV blood (P O ) despite a normal PO 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 P O 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 at WT levels with hypoxia treatment. Although mild hypoxia (17% O ) has been shown to be an ineffective therapy for Ndufs4 mice, we find that when combined with 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. −/− −/− −/− −/− −/− −/− + −/− −/− + 2 2 2 2 ijv 2 2 ijv 2 2

Keywords

A-V difference; Arterial-venous difference; Arteriovenous difference; Brain; Hypoxia; Leigh syndrome; Metabolism; Metabolomics; NAD; Ndufs4; Niacin; Nicotinamide adenine dinucleotide; Nicotinic acid; O2; Oxygen

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Molecular Genetics

Language

English

UNLV article access

Search your library

Share

COinS