Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway

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.

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

“…reported that iron overload damages MSC through AMPK/MFF/Drp1 pathway in MDS. 27 Thus, further research should investigate the effect of iron overload on the BM microenvironment in MDS.…”

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

“…Drp1 is activated and causes the fragmentation of mitochondria in neuronal cells ( 95 ). This is linked to iron overload, AMPK activation, MFF ( 96 ), and ubiquitination of A-kinase anchor protein 121 ( 97 ). Conversely, ROS induced mitophagy is suppressed by depleting Drp1 ( 98 ).…”

Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients

“…Repeated blood transfusion could accelerate iron absorption, which results in iron overload in some patients. Iron overload can increase the production of mitochondrial reactive oxygen species (ROS), induce the dysfunction of mesenchymal stem cells [8], promote erythroid apoptosis through regulating HIF-1a/ROS signalling pathway in MDS patients [9], injure the function of MDS-derived mesenchymal stromal cells (MSCs) and promote mitochondrial fragmentation in MSCs from MDS patients [10,11]. In light of this, we could speculate that the deterioration of anaemia in iron overloaded MDS patients may be related to the injury of hematopoietic cell and the abnormality of apoptosis.…”