Novel mitochondrion‐targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1‐mediating mitophagy in HCC

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.

Construction of a Myc-associated ceRNA network reveals a prognostic signature in hepatocellular carcinoma

“…The development of high-throughput transcriptome sequencing technologies and the ceRNA hypothesis have been proposed, in which lncRNAs and mRNAs interact with each other through shared miRNAs. 56 , 57 , 58 , 59 Recently, studies have been conducted to construct a ceRNA network between HCC tissues and adjacent nontumor liver tissues. 60 The molecular mechanisms of ceRNA associated with Myc remain unclear in HCC.…”

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

“…In recent years, the development of mitochondrial-based strategies has offered beneficial effects in metabolic diseases [ 11 ], to the extent that they may represent an interesting avenue to pursue for NAFLD-related HCC treatment, either as prophylaxis or patient care. Wang’s research group recently introduced the tri-phenyl-phosphine (TPP) groups into the copper–terpyridine complex, thus generating a novel molecule, called CTB, which exhibits mitochondrial-targeting properties [ 244 ]. CTB administration in HepG2 cells inhibits aerobic glycolysis and promotes DRP1 recruiting and the opening of mitochondrial pores, thus contributing to the activation of fission and mitophagy [ 244 ].…”

“…Wang’s research group recently introduced the tri-phenyl-phosphine (TPP) groups into the copper–terpyridine complex, thus generating a novel molecule, called CTB, which exhibits mitochondrial-targeting properties [ 244 ]. CTB administration in HepG2 cells inhibits aerobic glycolysis and promotes DRP1 recruiting and the opening of mitochondrial pores, thus contributing to the activation of fission and mitophagy [ 244 ]. Furthermore, CTB affects TERT methylation and expression, leading to the inhibition of both cell senescence and the growth of implanted tumors in mice [ 245 ].…”

An Integrated Network, RNA Sequencing, and Experiment Pharmacology Approach Reveals the Active Component, Potential Target, and Mechanism of Gelsemium elegans in the Treatment of Colorectal Cancer

“…HK2 is particularly important for the catabolism of glucose as it is the first enzyme of glycolysis (16). Moreover, HK2 is located on the outer membrane of the mitochondria via its binding to VDAC-1 to exert it biological function (17). The immunofluorescence was performed to detect the change of both HK2-mitochondria and HK2-VDAC-1 association of CRC cells.…”