| First Author | Lee CF | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 3073 |
| PubMed ID | 30816177 | Mgi Jnum | J:276123 |
| Mgi Id | MGI:6304737 | Doi | 10.1038/s41598-019-39419-4 |
| Citation | Lee CF, et al. (2019) Targeting NAD(+) Metabolism as Interventions for Mitochondrial Disease. Sci Rep 9(1):3073 |
| abstractText | 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. |
