The CD38 glycohydrolase and the NAD sink: Implications for pathological conditions

Julianna D. Zeidler, Kelly A. Hogan, Guillermo Agorrody, Thais R. Peclat, Sonu Kashyap, Karina S. Kanamori, Lilian Sales Gomez, Delaram Z. Mazdeh, Gina M. Warner, Katie L. Thompson, Claudia C.S. Chini, Eduardo Nunes Chini

Research output: Contribution to journalReview articlepeer-review


Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

Original languageEnglish (US)
Pages (from-to)C521-C545
JournalAmerican Journal of Physiology - Cell Physiology
Issue number3
StatePublished - Mar 2022


  • CD38
  • NAD metabolism
  • diseases

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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