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

Autor: Sida Zhao, Juan Guo, Qingqing Zheng, Chao Xiao, Chengming Fei, Chunkang Chang, Lingyun Wu, Xiao Li, Youshan Zhao, Dong Wu
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Dynamins
0301 basic medicine
Cancer Research
Mitochondrial fission factor
Primary Cell Culture
Immunology
Apoptosis
AMP-Activated Protein Kinases
Deferoxamine
Iron Chelating Agents
Ferric Compounds
Mitochondrial Dynamics
Article
Cell Line
GTP Phosphohydrolases
Electron Transport
Mitochondrial Proteins
03 medical and health sciences
Cellular and Molecular Neuroscience
Adenosine Triphosphate
Humans
Viability assay
RNA
Small Interfering
lcsh:QH573-671
Protein kinase A
Chemistry
lcsh:Cytology
Autophagy
Respiratory chain complex
Membrane Proteins
AMPK
Mesenchymal Stem Cells
Cell Biology
Mitochondria
Cell biology
Quaternary Ammonium Compounds
030104 developmental biology
Electron Transport Chain Complex Proteins
Gene Expression Regulation
Case-Control Studies
Myelodysplastic Syndromes
Mitochondrial fission
Reactive Oxygen Species
Microtubule-Associated Proteins
Signal Transduction
Zdroj: Cell Death and Disease, Vol 9, Iss 5, Pp 1-12 (2018)
Cell Death & Disease
ISSN: 2041-4889
Popis: 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.
Databáze: OpenAIRE
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