Novel mitochondrion‐targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1‐mediating mitophagy in HCC
Identifieur interne : 000092 ( an2020/Analysis ); précédent : 000091; suivant : 000093Novel mitochondrion‐targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1‐mediating mitophagy in HCC
Auteurs : Mengmeng Li ; Jiangjuan Shao ; Zijian Guo ; Chun Jin ; Ling Wang ; Feixia Wang ; Yan Jia ; Zhenzhu Zhu ; Ziji Zhang ; Feng Zhang ; Shizhong Zheng ; Xiaoyong WangSource :
- Journal of Cellular and Molecular Medicine [ 1582-1838 ] ; 2020.
Abstract
[Cu(ttpy‐tpp)Br2]Br (abbreviated as CTB) is a novel mitochondrion‐targeting copper(II) complex synthesized by our research group, which contains tri‐phenyl‐phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti‐tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co‐immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co‐ordinately promoted dynamin‐related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2‐mediated mitophagy and Drp1‐regulated mitochondrial fission.
Url:
DOI: 10.1111/jcmm.14971
PubMed: 31994339
PubMed Central: 7077532
Affiliations:
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type="abstract" xml:lang="en"><title>Abstract</title><p>[Cu(ttpy‐tpp)Br<sub>2</sub>]Br (abbreviated as CTB) is a novel mitochondrion‐targeting copper(II) complex synthesized by our research group, which contains tri‐phenyl‐phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti‐tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co‐immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co‐ordinately promoted dynamin‐related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2‐mediated mitophagy and Drp1‐regulated mitochondrial fission.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Guo, Zijian" sort="Guo, Zijian" uniqKey="Guo Z" first="Zijian" last="Guo">Zijian Guo</name><name sortKey="Jia, Yan" sort="Jia, Yan" uniqKey="Jia Y" first="Yan" last="Jia">Yan Jia</name><name sortKey="Jin, Chun" sort="Jin, Chun" uniqKey="Jin C" first="Chun" last="Jin">Chun Jin</name><name sortKey="Li, Mengmeng" sort="Li, Mengmeng" uniqKey="Li M" first="Mengmeng" last="Li">Mengmeng Li</name><name sortKey="Shao, Jiangjuan" sort="Shao, Jiangjuan" uniqKey="Shao J" first="Jiangjuan" last="Shao">Jiangjuan Shao</name><name sortKey="Wang, Feixia" sort="Wang, Feixia" uniqKey="Wang F" first="Feixia" last="Wang">Feixia Wang</name><name sortKey="Wang, Ling" sort="Wang, Ling" uniqKey="Wang L" first="Ling" last="Wang">Ling Wang</name><name sortKey="Wang, Xiaoyong" sort="Wang, Xiaoyong" uniqKey="Wang X" first="Xiaoyong" last="Wang">Xiaoyong Wang</name><name sortKey="Zhang, Feng" sort="Zhang, Feng" uniqKey="Zhang F" first="Feng" last="Zhang">Feng Zhang</name><name sortKey="Zhang, Ziji" sort="Zhang, Ziji" uniqKey="Zhang Z" first="Ziji" last="Zhang">Ziji Zhang</name><name sortKey="Zheng, Shizhong" sort="Zheng, Shizhong" uniqKey="Zheng S" first="Shizhong" last="Zheng">Shizhong Zheng</name><name sortKey="Zhu, Zhenzhu" sort="Zhu, Zhenzhu" uniqKey="Zhu Z" first="Zhenzhu" last="Zhu">Zhenzhu Zhu</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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