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

Blood. 2014 Jan 2;123(1):41-50. doi: 10.1182/blood-2013-06-508333. Epub 2013 Nov 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Cycle
  • Colony-Forming Units Assay
  • Flow Cytometry
  • Gene Expression Regulation*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / physiology*
  • Hematopoietic Stem Cells / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / physiology*
  • Oxidative Stress*
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology

Substances

  • Antioxidants
  • Carrier Proteins
  • HSP70 Heat-Shock Proteins
  • Hspa9 protein, mouse
  • Oncogene Proteins
  • Pyridines
  • Reactive Oxygen Species
  • Thiazoles
  • MKT 077
  • Peroxiredoxins
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1