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

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

  • Cell Death Dis. 2018 May 1;9(5):515. doi: 10.1038/s41419-018-0552-7.
Qingqing Zheng 1 Youshan Zhao 1 Juan Guo 1 Sida Zhao 1 Chengming Fei 1 Chao Xiao 1 Dong Wu 1 Lingyun Wu 1 Xiao Li 1 Chunkang Chang 2
Affiliations

Affiliations

  • 1 Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
  • 2 Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. changchunkang@sjtu.edu.en.
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.

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