The iNADequacy of renal cell metabolism: modulating NAD+ biosynthetic pathways to forestall kidney diseases

Perico L, Benigni A

Abstract

Since its discovery a century ago as a cofactor in the process of fermentation, nicotinamide adenine dinucleotide (NAD+) has received considerable attention in biomedical research. Major breakthroughs in our understanding of the biological role of NAD+ were provided in the 1930s by Otto Warburg, who significantly advanced our understanding of its chemistry and cellular functions. NAD+ is a hydride acceptor that, along with its reduced form, NADH, is vital to the reduction-oxidation (redox) reactions in metabolic processes, including glycolysis and mitochondrial oxidative phosphorylation (Figure 1a). Additional functions of NAD+ have been recognized over the last 2 decades, with the identification of several proteins that consume NAD+ to sustain their proper enzymatic activity (Figure 1b). Under physiological conditions, the available NAD+ cellular pool is the result of a steady balance between consumption and generation, the latter carried out through either a de novo pathway from tryptophan or a salvage pathway recycling nicotinamide back to NAD+ (Figure 1c). Alterations to this tight equilibrium decrease NAD+ content, which has been associated with the development of a wide range of diseases. In line with these findings, a large body of evidence has established that replenishing cellular NAD+ is a beneficial therapeutic intervention in a variety of pathogenic processes, although the protective mechanisms remain elusive.

JOURNAL

Kidney International