Depletion of nicotinamide adenine dinucleotide (NAD ⁺ ), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD ⁺ homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD ⁺ homeostasis, such as increased NAD ⁺ consumption or dietary deficiency of its vitamin B3 precursors. NAD ⁺ depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age‐related, diseases. Here, we discuss NAD ⁺ biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD ⁺ metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD ⁺ repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD ⁺ ‐enhancing agents.

Members of the ribonuclease III (RNase III) family regulate gene expression by processing double-stranded RNA (dsRNA). This family includes eukaryotic Dicer and Drosha enzymes that generate small dsRNAs in the RNA interference (RNAi) pathway. The fungus Mucor lusitanicus, which causes the deadly infection mucormycosis, has a complex RNAi system encompassing a non-canonical RNAi pathway (NCRIP) that regulates virulence by degrading specific mRNAs. In this pathway, Dicer function is replaced by R3B2, an atypical class I RNase III, and small single-stranded RNAs (ssRNAs) are produced instead of small dsRNA as Dicer-dependent RNAi pathways. Here, we show that R3B2 forms a homodimer that binds to ssRNA and dsRNA molecules, but exclusively cuts ssRNA, in contrast to all known RNase III. The dsRNA cleavage inability stems from its unusual RNase III domain (RIIID) because its replacement by a canonical RIIID allows dsRNA processing. A crystal structure of R3B2 RIIID resembles canonical RIIIDs, despite the low sequence conservation. However, the groove that accommodates dsRNA in canonical RNases III is narrower in the R3B2 homodimer, suggesting that this feature could be responsible for the cleavage specificity for ssRNA. Conservation of this activity in R3B2 proteins from other mucormycosis-causing Mucorales fungi indicates an early evolutionary acquisition.