Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease
Open Access
- 28 February 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 9 (1), 1-10
- https://doi.org/10.1038/s41598-019-39419-4
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.Keywords
This publication has 44 references indexed in Scilit:
- HIF1α Protein Stability Is Increased by Acetylation at Lysine 709Journal of Biological Chemistry, 2012
- Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease modelThe Journal of cell biology, 2011
- Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to StressMolecular Cell, 2010
- Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndromeProceedings of the National Academy of Sciences of the United States of America, 2010
- The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling PathwaysEndocrine Reviews, 2010
- NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvementMolecular Genetics and Metabolism, 2009
- Mice with Mitochondrial Complex I Deficiency Develop a Fatal EncephalomyopathyCell Metabolism, 2008
- The epidemiology of mitochondrial disorders—past, present and futureBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2004
- Magnitude and significance of NAD turnover in human cell line D98/AH2Nature, 1976
- The biosynthesis and turnover of nicotinamide adenine dinucleotide in enucleated culture cellsJournal of Cellular Physiology, 1974