Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease

• Published in: Scientific reports Vol. 9; no. 1; p. 3073
• Main Authors: Lee, Chi Fung, Caudal, Arianne, Abell, Lauren, Nagana Gowda, G. A., Tian, Rong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2019; Nature Publishing Group
• Subjects: 64/60; 692/4017; 692/699/375/2609; 82/1; 82/29; Acidosis; Animals; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Female; Humanities and Social Sciences; Ketoglutaric acid; Lactic acidosis; Leigh Disease - drug therapy; Leigh Disease - genetics; Leigh Disease - metabolism; Life span; Longevity - drug effects; Male; Metabolites; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Molecular Targeted Therapy; multidisciplinary; NAD; NAD - metabolism; Neurological diseases; Nicotinamide; Nicotinamide Mononucleotide - therapeutic use; Phenotypes; Rodents; Science; Science (multidisciplinary); Skeletal muscle; Supplements; Therapeutic applications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-39419-4

Leigh syndrome is a mitochondrial disease characterized by neurological disorders, metabolic abnormality and premature death. There is no cure for Leigh syndrome; therefore, new therapeutic targets are urgently needed. In Ndufs4-KO mice, a mouse model of Leigh syndrome, we found that Complex I deficiency led to declines in NAD + levels and NAD + redox imbalance. We tested the hypothesis that elevation of NAD + levels would benefit Ndufs4-KO mice. Administration of NAD + precursor, nicotinamide mononucleotide (NMN) extended lifespan of Ndufs4-KO mice and attenuated lactic acidosis. NMN increased lifespan by normalizing NAD + redox imbalance and lowering HIF1a accumulation in Ndufs4-KO skeletal muscle without affecting the brain. NMN up-regulated alpha-ketoglutarate (KG) levels in Ndufs4-KO muscle, a metabolite essential for HIF1a degradation. To test whether supplementation of KG can treat Ndufs4-KO mice, a cell-permeable KG, dimethyl ketoglutarate (DMKG) was administered. DMKG extended lifespan of Ndufs4-KO mice and delayed onset of neurological phenotype. This study identified therapeutic mechanisms that can be targeted pharmacologically to treat Leigh syndrome.