干细胞衰老。线粒体未折叠蛋白反应介导的代谢检查点调节造血干细胞衰老。
Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging.
作者信息
Mohrin Mary, Shin Jiyung, Liu Yufei, Brown Katharine, Luo Hanzhi, Xi Yannan, Haynes Cole M, Chen Danica
机构信息
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.
出版信息
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.
摘要
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。
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本文引用的文献
1
A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function.SIRT7 依赖性乙酰化开关的 GABPβ1 控制线粒体功能。
Cell Metab. 2014 Nov 4;20(5):856-869. doi: 10.1016/j.cmet.2014.08.001. Epub 2014 Sep 4.
2
Stem cell aging: mechanisms, regulators and therapeutic opportunities.干细胞衰老：机制、调节因子和治疗机会。
Nat Med. 2014 Aug;20(8):870-80. doi: 10.1038/nm.3651.
3
Sirtuins: guardians of mammalian healthspan.沉默调节蛋白：哺乳动物健康寿命的守护者。
Trends Genet. 2014 Jul;30(7):271-86. doi: 10.1016/j.tig.2014.04.007. Epub 2014 May 28.
4
SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.SIRT7 通过抑制 Myc 活性来抑制内质网应激，预防脂肪性肝病。
Cell Rep. 2013 Nov 14;5(3):654-665. doi: 10.1016/j.celrep.2013.10.007. Epub 2013 Nov 7.
5
FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis.FOXO3 与 ASCL1 全基因组共享共同靶点，并抑制 ASCL1 依赖性神经发生。
Cell Rep. 2013 Aug 15;4(3):477-91. doi: 10.1016/j.celrep.2013.06.035. Epub 2013 Jul 25.
6
Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging.染色质修饰作为肌肉干细胞静止和衰老的决定因素。
Cell Rep. 2013 Jul 11;4(1):189-204. doi: 10.1016/j.celrep.2013.05.043. Epub 2013 Jun 27.
7
The hallmarks of aging.衰老的特征。
Cell. 2013 Jun 6;153(6):1194-217. doi: 10.1016/j.cell.2013.05.039.
8
Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond.评估和应对线粒体功能障碍：线粒体未折叠蛋白反应及其他。
Trends Cell Biol. 2013 Jul;23(7):311-8. doi: 10.1016/j.tcb.2013.02.002. Epub 2013 Mar 13.
9
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Cell Stem Cell. 2013 Feb 7;12(2):152-65. doi: 10.1016/j.stem.2013.01.001.
10
SIRT3 reverses aging-associated degeneration.SIRT3 逆转与衰老相关的退行性变。
Cell Rep. 2013 Feb 21;3(2):319-27. doi: 10.1016/j.celrep.2013.01.005. Epub 2013 Jan 31.
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