CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level.

Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), a mammalian orthologue of drosophila flamingo, belongs to the cadherin subfamily. CELSR2 mainly function in neural development and cilium polarity. Recent studies showed that the CELSR2 gene is related to many human diseases, including coronary artery disease, idiopathic scoliosis, and cancer. Genome-Wide Association Studies data showed that SNP in the CELSR2-PSRC1-SORT1 gene loci has a strong association with circulating lipid levels and coronary artery disease. However, the function and underlying mechanism of CELSR2 in hepatic lipid metabolism remain unknown. Here, we found that CELSR2 expression is decreased in the liver of NAFLD/NASH patients and db/db mice. Depletion of CELSR2 significantly decreased the lipid accumulation in hepatocytes by suppressing the expression of lipid synthesis enzymes. Moreover, CELSR2 deficiency impaired the physiological unfolded protein response (UPR), which damages the ER homeostasis, and elevates the reactive oxygen species (ROS) level by decreasing the antioxidant expression. Scavenging of ROS by N-acetylcysteine treatment could restore the decreased lipid accumulation of CELSR2 knockdown cells. Furthermore, CELSR2 loss impaired cell survival by suppressing cell proliferation and promoting apoptosis. Our results uncovered a new role of CELSR2 in regulating lipid homeostasis and UPR, suggesting CELSR2 may be a new therapeutic target for non-alcoholic fatty liver disease.

C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A.

C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.

Topochemical synthesis of Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites as lithium-ion battery anodes with fast Li+ migration and giant pseudocapacitance via the mesocrystalline effect.

Transition metal compounds are a promising substitute for graphite as lithium-ion battery (LIB) anodes. In this study, mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites were synthesized using a layered titanic acid H1.07Ti1.73O4 (HTO) precursor. The ß-MnOOH layer is intercalated into the interlayer of HTO by Mn2+-exchange treatment of H2O2-intercalated HTO, which includes ion-exchange of Mn2+ with H+ in the interlayer and oxidation of Mn2+ to the ß-MnOOH layer by H2O2 in the interlayer space. Mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites with a platelike morphology were obtained by heat treatment of a sandwich layered HTO/ß-MnOOH under air and H2/Ar atmospheres, respectively. The electrochemical results suggest that the mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites show a synergistic effect for enhanced cycling stability and a mesocrystalline effect for enhanced discharge-charge specific capacity by improving the Li+ mobility and enhancing the pseudocapacitance of the mesocrystalline nanocomposites as LIB anode materials. The discharge-charge specific capacity of the mesocrystalline Mn2O3/TiO2 nanocomposite is twice as high as that of the polycrystalline one caused by the mesocrystalline effect. Furthermore, the synergistic and mesocrystalline effects led to a stable large discharge-charge specific capacity of 710 mA h g-1 for the mesocrystalline Mn2O3/TiO2 nanocomposite. This work proposes a new concept to enhance the performance of anode materials for LIBs using mesocrystalline materials.

CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response.

Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson's disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first "mtISR suppressor" localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.

Remarkably enhanced ion-exchange capacity of H2O2-intercalated layered titanate.

H2O2-intercalated layered titanate H1.07Ti1.73O4 (H2O2-HTO) exhibits a dramatically enhanced ion-exchange capacity and remarkably improved reaction rate with various divalent cations. The intercalation can increase the negative charge density of the TiO6 octahedral layer and the number of ion-exchangeable H+ by forming a Ti(iv)-O-O-H bond that is the driving force to change the ion exchange performance.