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

• Published in: Molecular genetics and metabolism Vol. 133; no. 1; pp. 83 - 93
• Main Authors: Grange, Robert M.H., Sharma, Rohit, Shah, Hardik, Reinstadler, Bryn, Goldberger, Olga, Cooper, Marissa K., Nakagawa, Akito, Miyazaki, Yusuke, Hindle, Allyson G., Batten, Annabelle J., Wojtkiewicz, Gregory R., Schleifer, Grigorij, Bagchi, Aranya, Marutani, Eizo, Malhotra, Rajeev, Bloch, Donald B., Ichinose, Fumito, Mootha, Vamsi K., Zapol, Warren M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2021
• Subjects: A-V difference; Animals; Arterial-venous difference; Arteriovenous difference; Brain; Brain - metabolism; Brain - pathology; Cell Hypoxia - physiology; Disease Models, Animal; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Humans; Hypoxia; Leigh Disease - genetics; Leigh Disease - metabolism; Leigh Disease - therapy; Leigh syndrome; Metabolism; Metabolomics; Mice; Mitochondria; NAD; NAD - deficiency; NAD - genetics; Ndufs4; Neurodegenerative Diseases; Niacin; Nicotinamide adenine dinucleotide; Nicotinic acid; Oxygen; Oxygen - metabolism; Respiration - genetics; Brain; Metabolomics; O2; Partial pressure of oxygen; Nicotinic acid; Oxidized nicotinamide adenine dinucleotide; Arterial-venous difference; Arteriovenous difference; O2 content in arterial blood; Vehicle; Leigh syndrome; Arterial-internal jugular venous difference; Reduced nicotinamide adenine dinucleotide; Brain tissue PO2; Ndufs4; Oxygen; Lactate/pyruvate ratio; Internal Jugular Vein; NADH:ubiquinone oxidoreductase subunit S4; O2 content in IJV blood; Metabolism; O2 saturation of hemoglobin in IJV blood; Niacin; Partial pressure of oxygen in IJV blood; NAD; A-V difference; O2 saturation of hemoglobin in arterial blood; Partial pressure of oxygen in arterial blood; Nicotinamide adenine dinucleotide; Hypoxia; Liquid chromatography–mass spectrometry; O
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2021.03.005

Leigh syndrome is a severe mitochondrial neurodegenerative disease with no effective treatment. In the Ndufs4−/− mouse model of Leigh syndrome, continuously breathing 11% O2 (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% O2. Compared to WT control mice, Ndufs4−/− mice breathing air have reduced brain O2 consumption as evidenced by an elevated partial pressure of O2 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 at WT levels with hypoxia treatment. Although mild hypoxia (17% O2) 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.