[HTML][HTML] Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease

CF Lee, A Caudal, L Abell, GA Nagana Gowda… - Scientific reports, 2019 - nature.com
CF Lee, A Caudal, L Abell, GA Nagana Gowda, R Tian
Scientific reports, 2019nature.com
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) …
Abstract
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.
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