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

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Science  20 Mar 2015:
Vol. 347, Issue 6228, pp. 1374-1377
DOI: 10.1126/science.aaa2361

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Keeping stem cells in tip top condition

Stem cells are important in the maintenance and growth of tissues. For the health of the organism as a whole, it is important that only healthy stem cells be used. Mohrin et al. elucidated a regulatory branch of the mitochondrial unfolded protein response that is coupled to cellular energy metabolism and proliferation in stem cells (see the Perspective by Ocampo and Belmonte). Mitochondrial protein folding stress triggered a metabolic checkpoint that regulates the cell cycle. Deregulation of this pathway interfered with stem cell quiescence and compromised regenerative function.

Science, this issue p. 1374; see also p. 1319


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 (UPRmt), 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 (PFSmt), 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 UPRmt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.

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