De novo NAD+ synthesis enhances mitochondrial function and improves health

Abstract

Nicotinamide adenine dinucleotide (NAD + ) is a cosubstrate for several enzymes, including the sirtuin family of NAD + -dependent protein deacylases. Beneficial effects of increased NAD + levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits the proportion of ACMS able to undergo spontaneous cyclisation in the de novo NAD + synthesis pathway, controls cellular NAD + levels via an evolutionary conserved mechanism from C. elegans to the mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD + synthesis and SIRT1 activity, ultimately enhancing mitochondrial function. We furthermore characterized a series of potent and selective ACMSD inhibitors, which, given the restricted ACMSD expression in kidney and liver, are of high therapeutic interest to protect these tissues from injury. ACMSD hence is a key modulator of cellular NAD + levels, sirtuin activity, and mitochondrial homeostasis in kidney and liver.

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

“…NAD+ was extracted using acidic and alkaline extraction methods, respectively. Tissue NAD+ was analyzed with mass spectrometry, as previously described (Katsyuba et al, ).…”

SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

“…In brief, NOX2-dependent oxidative stress triggered progerin-associated premature senescence to result in defenestration in HSECs via F-actin remodeling. SIRT1, a class Ⅲ histone deacetylase, serves as an important modulator of metabolism, cellular survival, and lifespan [10]. Some recent evidence reports that the activation of SIRT1 confers protective effects on hepatic senescence and HSCs activation to ameliorate liver fibrosis [11,12].…”

“…Sirtuin 1 (SIRT1) is an important protector against oxidative stress and senescence to reverse the progression of chronic liver diseases [10]. Recent researches emphasize that overexpressing or activating SIRT1 inhibits hepatic senescence and activation of HSCs to ameliorate liver fibrosis [11,12].…”

Niacin: an old lipid drug in a new NAD+ dress

“…Interestingly, NAD + -consuming enzymes, including the poly(ADP-ribose)-polymerase (PARP) family, can be overactivated in some diseases by lipid overload and, hence, could be responsible for NAD + depletion, as observed in steatotic livers (57). In line, several different approaches to increase NAD + levels, including stimulation of NAD + biosynthesis, e.g., by administration of NR, as well as inhibition of PARPs, were shown to protect from hepatic lipid accumulation in the case of nonalcoholic fatty liver disease (57)(58)(59)(60) and alcoholic liver disease (61). Although administration of NAM failed to reproduce the benefits of niacin due to end-product inhibition of sirtuin activity (62), NR potently increases the use of lipids as energy substrates and ameliorates cholesterol profiles in mice (63), reminiscent to what is seen upon niacin treatment.…”

“…2), leads to increased NAD + levels and subsequently promotes SIRT1-target gene expression in adipose tissues and overall energy expenditure (64). Importantly, recent publications also highlighted that raising NAD + levels provides protection against acute kidney injury in mice (59,65), which might explain in part the beneficial impact of niacin on kidney function in patients with CKD and ESRD (27)(28)(29)(30)(31)(32)(33)(34). Despite the wealth of preclinical studies studying the effects of NAD + boosting on lipid metabolism, metabolic control, and longevity, large clinical trials focused on the consequences of NAD + boosting on lipid homeostasis and CVDs in humans are still pending.…”