Date Published: March 24, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Mary Mohrin, Andrew Widjaja, Yufei Liu, Hanzhi Luo, Danica Chen.
The mitochondrial unfolded protein response (UPRmt), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues. Despite the emerging genetic evidence implicating the UPRmt in stem cell maintenance, the underlying molecular mechanism is unknown. While it has been speculated that the UPRmt is activated upon stem cell transition from quiescence to proliferation, the direct evidence is lacking. In this study, we devised three experimental approaches that enable us to monitor quiescent and proliferating hematopoietic stem cells (HSCs) and provided the direct evidence that the UPRmt is activated upon HSC transition from quiescence to proliferation, and more broadly, mitochondrial integrity is actively monitored at the restriction point to ensure metabolic fitness before stem cells are committed to proliferation.
Adult stem cells persist throughout the entire lifespan of an organism to repair tissue damage and maintain tissue homeostasis. Among their evolved adaptations are elaborate cellular protective programs that ensure stem cell integrity, tissue homeostasis, and organismal survival (Biteau, Hochmuth & Jasper, 2008; Brown et al., 2013; Ito et al., 2004; Rando, 2006; Renault et al., 2009; Rossi, Jamieson & Weissman, 2008; Rossi et al., 2007; Sahin & Depinho, 2010; Sperka, Wang & Rudolph, 2012; Walter et al., 2015). The mitochondrial unfolded protein response (UPRmt), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues (Berger et al., 2016; Mohrin et al., 2015; Zhang et al., 2016). This protective program is dysregulated during physiological aging, contributing to the functional deterioration of stem cells, tissue degeneration, and shortened organismal lifespan (Mohrin et al., 2015; Zhang et al., 2016). In addition to the UPRmt, deregulation of compensatory mitochondrial protective programs such as mitophagy and mitochondrial dynamics leads to compromised stem cells, further underscoring the importance of mitochondrial integrity in stem cell maintenance (Ho et al., 2017; Ito et al., 2016; Luchsinger, de Almeida, Corrigan, Mumau & Snoeck, 2016; Vannini et al., 2016).