Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, PL02

Plenary Lecture

Targeting mitochondria for therapy

R. Tian1

1. University of Washington, Seattle, Washington, United States.


Mitochondrial dysfunction is a recognized mechanism in the pathogenesis of a number of chronic diseases including neurodegeneration, diabetes and cardiovascular diseases. However, there has been very limited success in drug development for mitochondrial dysfunction. Novel therapeutic targets are urgently needed. In a mouse model of mitochondrial Complex-I deficiency due to deletion of Ndufs4 we found that decreased NADH oxidation in mitochondria led to lower NAD/NADH ratio and reduced NAD-dependent protein deacetylation. The resultant hyperacetylation of mitochondrial proteins rendered the heart highly sensitive to additional stress. Elevation of NAD+ level by pharmacological or genetic strategies in mouse models of mitochondrial dysfunction could normalize the protein acetylation and restore the stress response in the heart. Furthermore, we have identified a number of mechanisms by which NAD+-sensitive protein acetylation contributes to the hypersensitivity to stress. Supplementation of nicotinamide mononucleotide (NMN), a NAD+ precursor, in a mouse model of Leigh syndrome, reduced blood lactate level and significantly extended lifespan. NMN also restored the NAD/NADH ratio in the heart with pathological hypertrophy and blunted the course of heart failure. The safety and tolerability of increasing intracellular NAD+ level by nicotinamide riboside (NR) is now being investigated in heart failure patients. Collectively, these observations identify NAD(H) level and multiple NAD+-sensitive mechanisms as viable therapeutic targets for mitochondrial dysfunction.

Where applicable, experiments conform with Society ethical requirements