An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging

Nat Aging. 2024 Oct;4(10):1384-1393. doi: 10.1038/s43587-024-00670-8. Epub 2024 Jul 23.

Abstract

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.

MeSH terms

  • ADP-ribosyl Cyclase 1* / metabolism
  • Aging* / metabolism
  • Aging* / physiology
  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology
  • Hematopoietic Stem Cells* / drug effects
  • Hematopoietic Stem Cells* / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria* / drug effects
  • Mitochondria* / metabolism
  • NAD* / metabolism

Substances

  • ADP-ribosyl Cyclase 1
  • NAD
  • Calcium
  • Calcium Channels
  • Cd38 protein, mouse
  • mitochondrial calcium uniporter
  • Membrane Glycoproteins