Abstract
Leigh syndrome is a mitochondrial disease characterized by neurological disorders, metabolic abnormalities, 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 the elevation of NAD+ levels would benefit Ndufs4-KO mice. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN) extended the lifespan of Ndufs4-KO mice and attenuated lactic acidosis. NMN increases 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 the lifespan of Ndufs4-KO mice and delayed the onset of neurological phenotype. This study identified therapeutic mechanisms that can be targeted pharmacologically to treat Leigh syndrome.
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395802/
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