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NMN extended lifespan of mice with a mitochondria disorder called Leigh syndrome


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#1 Phoebus

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Posted 06 March 2019 - 03:10 PM


Article OPEN Published: 

28 February 2019


Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease

Scientific Reportsvolume 9, Article number: 3073 (2019




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.


Pretty obvious they are gearing up to try this therapy with humans who have various mito disorders. Wonder how long before human trials? 

Edited by Phoebus, 06 March 2019 - 03:09 PM.

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#2 Phoebus

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Posted 06 March 2019 - 03:26 PM



Therapeutic benefits of NMN were mediated by elevation of alpha-ketoglutarate (KG) levels and suppression of hypoxic signaling.


So thats the mechanism they seem to be focusing on here. 



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