Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease.

Scientific Reports
Chi Fung LeeRong Tian

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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Citations

Jul 8, 2020·Pharmaceutics·Jeffrey FarooqCesar V Borlongan
Jan 20, 2021·The Journal of Clinical Investigation·Marjan Gucek, Michael N Sack
Jan 20, 2021·Nature Metabolism·Divakar S Mithal, Navdeep S Chandel
Aug 14, 2020·Experimental Gerontology·Marie BretonMathias Mericskay
Jan 25, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Karin TerburghRoan Louw
Apr 15, 2020·Mechanisms of Ageing and Development·Ruohan ZhangNuo Sun
Aug 2, 2020·Mitochondrion·Rebecca BornsteinSimon C Johnson
Feb 23, 2021·Oncotarget·Mikhail V Blagosklonny
Mar 24, 2021·Molecular Genetics and Metabolism·Robert M H GrangeWarren M Zapol
Mar 30, 2020·Cell·Oliver M RussellDoug M Turnbull
Sep 13, 2021·The FEBS Journal·Christopher F BennettPere Puigserver
Sep 28, 2021·Analytical Methods : Advancing Methods and Applications·Tianxiao YuJun Ge
Nov 19, 2021·Metabolomics : Official Journal of the Metabolomic Society·Karin TerburghRoan Louw

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Methods Mentioned

BETA
acetylation
Protein acetylation
Assay
NMR

Software Mentioned

Chenomx NMR Suite Professional
ImageJ
Bruker Topspin
Vevo 2100

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