Mohrin Mary, Shin Jiyung, Liu Yufei, Brown Katharine, Luo Hanzhi, Xi Yannan, Haynes Cole M, Chen Danica
Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Science. 2015 Mar 20;347(6228):1374-7. doi: 10.1126/science.aaa2361.
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.
成体干细胞的衰退是衰老相关的组织维持功能受损的主要原因。干细胞如何维持代谢稳态仍不清楚。在这里，我们发现了线粒体未折叠蛋白反应（UPR(mt)）的一个调控分支，它由SIRT7和NRF1的相互作用介导，并与细胞能量代谢和增殖相关联。SIRT7失活导致静止性降低、线粒体蛋白折叠应激（PFS(mt)）增加以及造血干细胞（HSC）的再生能力受损。在衰老的HSC中SIRT7表达降低，而SIRT7的上调改善了衰老HSC的再生能力。这些发现确定了UPR(mt)介导的代谢检查点失调是HSC衰老的一个可逆促成因素。
