Abstract
Iron overload (IO) has been reported to contribute to mesenchymal stromal cell (MSC) damage, but the precise mechanism has yet to be clearly elucidated. In this study, we found that IO increased cell apoptosis and lowered cell viability in MSCs, accompanied by extensive mitochondrial fragmentation and autophagy enhancement. All these effects were reactive oxygen species (ROS) dependent. In MSCs with IO, the ATP concentrations were significantly reduced due to high ROS levels and low electron respiratory chain complex (ETC) II/III activity. Reduced ATP phosphorylated AMP-activated protein kinase (AMPK). Activation of AMPK kinase complexes triggered mitochondrial fission. Moreover, gene knockout of AMPK via CRISPR/Cas9 reduced cell apoptosis, enhanced cell viability and attenuated mitochondrial fragmentation and autophagy caused by IO in MSCs. Further, AMPK-induced mitochondrial fragmentation of MSCs with IO was mediated via phosphorylation of mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for the GTPase dynamin-related protein 1 (Drp1). Gene knockdown of MFF reversed AMPK-induced mitochondrial fragmentation in MSCs with IO. In addition, MSCs from IO patients with myelodysplastic syndrome (MDS) showed increased cell apoptosis, decreased cell viability, higher ROS levels, lower ATP concentrations and increased mitochondrial fragmentation compared with MSCs from non-IO patients. In addition, iron chelation or antioxidant weakened the activity of the AMPK/MFF/Drp1 pathway in MDS-MSCs with IO from several patients, accompanied by attenuation of mitochondrial fragmentation and autophagy. Taken together, the AMPK/MFF/Drp1 pathway has an important role in the damage to MDS-MSCs caused by IO.
Highlights
In this study, we demonstrated that Iron overload (IO) causes extensive mitochondrial fragmentation and autophagy enhancement in Myelodysplastic syndrome (MDS)-mesenchymal stromal cell (MSC), which results in MDS-MSCs that are more prone to apoptosis and have a lower viability than bone marrow (BM)-MSCs from healthy controls and MDS patients without IO
The decrease in ATP levels leads to robust AMPK activation that in turn phosphorylates mitochondrial fission factor (MFF), which recruits the pro-fission molecule Drp[1] to mitochondria and allows unopposed mitochondrial fission
Mitochondrial dysfunction caused by the activity of the AMPK/MFF/Drp[1] pathway has an important role in cytotoxicity of MDS-MSCs with IO
Summary
Derived mesenchymal stromal cells (MDS-MSCs) with IO were deficient in proliferation and differentiation, and Official journal of the Cell Death Differentiation Association. MSCs are key functional components of the BM microenvironment and have an important role in supporting and regulating HSPCs via secretion of haematopoietic cytokines, chemokines and adhesion factors[8,9]. In addition to their supportive effects, MSCs may facilitate damage of HSPCs under some pathological circumstances. High levels of reactive oxygen species (ROS) caused by IO may be a crucial factor in harming the function of MSCs7,8,10,11. The specific associations between ROS and MSC damage have not been fully elucidated
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