Iron overload adversely effects bone marrow haematogenesis via SIRT-SOD2-mROS in a process ameliorated by curcumin

Shujuan Zhou,Songfu Jiang,Zhijian Shen,Kang Yu,Yifen Shi,Haige Ye,Ruye Ma,Jianping Shen,Shanhu Qian,Yongyong Ma,Yuqing Dong,Lan Sun,Shenghui Zhang,Siqian Wang

doi:10.1186/s11658-020-00244-7

Abstract

BackgroundIron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism.MethodsWe established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload.ResultsIron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy.ConclusionsOur results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.

Highlights

Iron overload is common in patients with haematological disorders due to long-term repeated red cell transfusion, congenital iron overload disease, and a subclass of anaemia characterised by ineffective haematogenesis, leading to excess iron deposition throughout the body
Iron overload can damage bone marrow In our cell model, we found that iron-overloaded Bone marrow mononuclear cell (BMMNC) showed decreased cell viability (Additional file 1: Fig. S1A), reduced cell proliferation activity (Additional file 1: Fig. S1B), and significantly increased intracellular Labile iron pools (LIP) (Additional file 1: Fig. S1C)
Iron overload can lead to bone marrow damage through autophagy We examined the expression of light chain 3 (LC3) as a marker of autophagy in iron-overloaded BMMNCs and found that the expression of LC3II increased with increasing ferric ammonium citrate (FAC) dose (Fig. 3a)

Summary

Introduction

Iron overload is common in patients with haematological disorders due to long-term repeated red cell transfusion, congenital iron overload disease, and a subclass of anaemia characterised by ineffective haematogenesis, leading to excess iron deposition throughout the body. This last form causes tissue damage and organ dysfunction and eventually leads to the mortality and morbidity associated with anaemia-related diseases [1, 2]. Sirutin 3 (SIRT3) is the main mitochondrial acetyl-lysine deacetylase It modulates multiple proteins, thereby controlling mitochondrial function and mROS generation [12]. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yetunknown mechanism

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Results

Conclusion