Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

Science. 2015 Mar 20;347(6228):1374-7. doi: 10.1126/science.aaa2361.

Abstract

Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Checkpoints*
  • Cellular Senescence*
  • Energy Metabolism
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Nuclear Respiratory Factor 1 / metabolism*
  • Protein Biosynthesis
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Unfolded Protein Response*

Substances

  • Mitochondrial Proteins
  • NRF1 protein, human
  • Nuclear Respiratory Factor 1
  • SIRT7 protein, human
  • Sirtuins