The Mitochondrial Deoxyguanosine Kinase is Required for Cancer Cell Stemness in Lung Adenocarcinoma

The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence

Inhibition Effect of Graphene Nanoplatelets on Electrical Degradation in Silicone Rubber

Silicone rubber (SIR) is widely used as an insulation material in high voltage cable accessories. Electrical tree is a typical electrical degradation and is easily initiated because of the distorted electric field. In this study, graphene nanoplatelets at contents of 0.001–0.010 wt % (0.00044–0.00436 vol %) were added into SIR to improve the electrical tree inhibiting ability. Scanning electron microscopy, conductivity and surface potential decay tests were conducted to analyze the characteristics of graphene/SIR nanocomposites. The typical electrical treeing experiment was employed to observe the electrical tree inhibition of graphene in SIR. The results show that graphene nanoplatelets were well dispersed in SIR. The conductivity was higher after the addition of graphene nanoplatelets, and the trap distribution was affected by graphene nanoplatelets. The tree was changed from a bush-branch structure to a bush structure after the addition of graphene. Tree inception voltage improved and reached the highest mean value at 0.003 wt %. The tree length was inhibited at 0.001 to 0.007 wt % and the lowest tree length occurred at 0.005 wt %

Simultaneous Interphase Optimizations on the Large-Area Anode and Cathode of High-Energy-Density Lithium-Ion Pouch Cells by a Multiple Additives Strategy

Prior to the maturation of next-generation energy storage devices, the actual lithium-ion batteries for commercial purposes are still expected to fulfill some critical requirements, among which the high energy density, wide operating temperature range, and related long-term cycling stability are the most challenging issues. Herein a multiple additives strategy is employed to simultaneously optimize the solid electrolyte interphase on the large-area anode and cathode in a 2 Ah artificial graphite (AGO/LiNi0.5Co0.2Mn0.3O2 (NCM523) pouch cell with high gravimetric (>260 Wh kg(-1)) and volumetric (>630 Wh L-1) energy density. By introducing a rational mixture of electrolyte additives, a highly sulfurized surface layer and a uniform and thin passivation layer are separately formed on the anode and cathode of the AGr/NCM523 pouch cell, exhibiting high storage stability at 60 degrees C, much improved discharge capacity at -10 and -20 degrees C, high anodic stability at high voltage of 4.4 V, and stable cyclic performance with a capacity retention of 85.5% after 500 cycles, significantly outperforming the value of 75.7% after only 200 cycles of the cell without additional additives. These results demonstrate the critical effect of simultaneous optimizations of anode and cathode interphase layers to construct stable high-energy-density lithium-ion pouch cells

Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments

The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

Abstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence