Role of ACMSD in regulation of NAD+ metabolism and mitochondrial function

Discovered in the beginning of the 20th century, nicotinamide adenine dinucleotide (NAD+) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of regulatory proteins that include most notoriously the sirtuin family of NAD+-dependent protein deacylases. Altered NAD+ metabolism is associated with many pathological conditions, including aging and obesity, while beneficial effects of increased NAD+ levels and subsequent sirtuin activation have been established across many different species. Due to their capacity to ameliorate mitochondrial homeostasis, organismal metabolism and lifespan, strategies aiming to boost NAD+ content possess a high therapeutic potential. This thesis describes a novel approach to increase NAD+ levels by stimulating its de novo biosynthesis from the amino acid tryptophan. The enzyme Aminocarboxymuconate Semialdehyde Decarboxylase (ACMSD) converts its substrate, ACMS, into the side branch of the pathway leading to its complete oxidation, consequently limiting the proportion of ACMS capable to generate NAD+. Since reducing ACMSD activity would prevent the flux of metabolites into the side branch and channel them towards NAD+ formation instead, the ultimate goal of this thesis was to establish the role of ACMSD in the control of the intracellular NAD+ content. First, by using genetic tools I found that reduction of ACMSD activity indeed boosts de novo NAD+ synthesis through a mechanism that is conserved from the worm C. elegans to the mouse. Beneficial effects associated with the observed increase in cellular NAD+ levels promoted mitochondrial biogenesis involving sirtuin activation. Secondly, I participated in the development of a panel of potent and selective ACMSD inhibitors. Given the restricted expression of ACMSD in the kidney and liver, its pharmacological inhibition can be a valuable strategy to increase NAD+ content in these tissues and to protect them from injury. After primary characterisation of the ACMSD inhibitors in cell models, I explored the therapeutic potential of the lead compounds to protect from non-alcoholic fatty liver disease and acute kidney injury in mice. Collectively, the data reported in this thesis describe ACMSD as an evolutionary conserved modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis. Through its impact on cellular NAD+ levels ACMSD inhibition is able to preserve the hepatic and renal function from injury.