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Mortalin and DJ-1 coordinately regulate hematopoietic stem cell function through the control of oxidative stress.

Abstract：

:Hematopoietic stem cells (HSCs) maintain stemness through various mechanisms that protect against stressful conditions. Heat shock proteins (HSPs) preserve cell homeostasis during stress responses through protein quality control, suggesting that HSPs may safeguard HSCs against numerous traumas. Here, we show that mortalin, a mitochondrial HSP, plays an essential role in maintaining HSC properties by regulating oxidative stress. Mortalin is primarily localized in hematopoietic stem and progenitor cell (HSPC) compartments. In this study, the inhibition of mortalin function caused abnormal reactive oxygen species (ROS) elevation in HSCs and reduced HSC numbers. Knockdown (KD) of mortalin in HSPCs impaired their ability to repopulate and form colonies. Moreover, mortalin-KD HSCs could not maintain quiescence and showed severe downregulation of cyclin-dependent kinase inhibitor- and antioxidant-related genes. Conversely, HSCs that overexpressed mortalin maintained a high reconstitution capacity and low ROS levels. Furthermore, DJ-1, one of the genes responsible for Parkinson's disease, directly bound to mortalin and acted as a negative ROS regulator. Using DJ-1-deficient mice, we demonstrated that mortalin and DJ-1 coordinately maintain normal ROS levels and HSC numbers. Collectively, these results indicate that the mortalin/DJ-1 complex guards against mitochondrial oxidative stress and is indispensable for the maintenance of HSCs.

journal_name

Blood

journal_title

Blood

authors

Tai-Nagara I,Matsuoka S,Ariga H,Suda T

doi

10.1182/blood-2013-06-508333

subject

Has Abstract

pub_date

2014-01-02 00:00:00

pages

41-50

issue

1

eissn

0006-4971

issn

1528-0020

pii

blood-2013-06-508333

journal_volume

123

pub_type

杂志文章

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