Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease

Chi Fung Lee,Lauren Abell,G A Nagana Gowda,Arianne Caudal,Rong Tian

doi:10.1038/s41598-019-39419-4

Chi Fung Lee, Lauren Abell + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-39419-4

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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.

Highlights

Apart from acting as an electron carrier in metabolic pathways, NAD+ is a co-substrate of several NAD+-dependent enzymes responsible for regulating protein post-translational modifications (PTMs) and DNA repair[4,5]
Similar to what was observed in the heart[18,19], the NAD+ redox imbalance was associated with protein hyperacetylation in Ndufs4-KO brain (Fig. 1C)
We delivered NAD+ precursor, nicotinamide mononucleotide (NMN), or vehicle via intraperitoneal injection, to Ndufs4-KO mice starting from postnatal day 21 (P-21) throughout their lifetime (Supplementary Fig. 2B)

Summary

Introduction

Apart from acting as an electron carrier in metabolic pathways, NAD+ is a co-substrate of several NAD+-dependent enzymes responsible for regulating protein post-translational modifications (PTMs) and DNA repair[4,5]. Recent studies showed that supplementation of NAD+ precursors in the salvage pathway is therapeutic for multiple pathologies[7,11,12]. We previously showed that C-I-deficiency in the heart of cardiac-specific Ndufs4-KO mice (cKO) led to elevated NADH levels, NAD(H) redox imbalance and protein hyperacetylation[8]. These biochemical changes contribute to the increased susceptibility of the heart to a variety of stresses, which can be rescued by increasing cellular NAD+ level. We tested the hypothesis that NAD(H) redox imbalance is a pathogenic mechanism in LS using Ndufs4-KO mice. We found that supplementation of the NAD+ precursor, nicotinamide mononucleotide (NMN), extended the lifespan of Ndufs4-KO mice. Our findings were further supported by the increased lifespan and the neurological benefits of KG supplementation in Ndufs4-KO mice

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Conclusion