Meet the authors: Yuqiu Sun and Hui Jiang.

We talk to first author Yuqiu Sun and corresponding author Hui Jiang about their paths in science, mentorship, and the exciting moments in the journey towards their paper "A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass" (this issue of Molecular Cell).

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.

Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.

eIF4EHP promotes Ldh mRNA translation in and fruit fly adaptation to hypoxia.

Hypoxia induces profound modifications in the gene expression program of eukaryotic cells due to lowered ATP supply resulting from the blockade of oxidative phosphorylation. One significant consequence of oxygen deprivation is the massive repression of protein synthesis, leaving a limited set of mRNAs to be translated. Drosophila melanogaster is strongly resistant to oxygen fluctuations; however, the mechanisms allowing specific mRNA to be translated into hypoxia are still unknown. Here, we show that Ldh mRNA encoding lactate dehydrogenase is highly translated into hypoxia by a mechanism involving a CA-rich motif present in its 3' untranslated region. Furthermore, we identified the cap-binding protein eIF4EHP as a main factor involved in 3'UTR-dependent translation under hypoxia. In accordance with this observation, we show that eIF4EHP is necessary for Drosophila development under low oxygen concentrations and contributes to Drosophila mobility after hypoxic challenge. Altogether, our data bring new insight into mechanisms contributing to LDH production and Drosophila adaptation to oxygen variations.

Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis.

Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs.

Neuroprotective effects of triterpenoid saponins from Medicago sativa L. against H2O2-induced oxidative stress in SH-SY5Y cells.

Medicago sativa L. is a forage legume plant widely distributed in all continents. Six new triterpenoid saponins, Medicagosides A-F (1-6) and five known ones (7-11) were isolated from M. sativa. Their structures were determined via HRESIMS, 1D and 2D NMR analysis. Biologically, all the isolates displayed neuroprotective activities against H2O2-induced damage in SH-SY5Y cells. Among them, compounds 1, 3-5 and 10 exhibited striking neuroprotective activities at 100 µM, restoring cell viability range from 79.66% to 89.03%, relative to 79.46% (100 µM) of Trolox used as the positive control.

Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression.

BACKGROUND: Tumor metastasis often occurs in hepatocellular carcinoma (HCC) and influences the patient's prognosis, and microRNAs are reported to play key roles in tumor metastasis. This study was conducted to explore the effect of microRNAs on HCC metastasis. METHODS: The levels of miR-181a in HCC tissues, adjacent tissues, metastatic HCC tissues, and non-metastatic HCC tissues at different stages were determined by qRT-PCR. Effect of miR-181a on the proliferation, invasion, and metastasis of HCC cells was estimated by cell counting kits-8 (CCK-8), wound-healing, and Transwell assays. Software analysis and luciferase assays were used to explore the target gene of miR-181a. RESULTS: MiR-181a was up-regulated in HCC tissues and its expression level in metastatic HCC tissues was much higher than in non-metastasis samples. PTEN was found to be a target gene of miR-181a. MiR-181a had multiple binding sites with the long non-coding RNA (lncRNA) XIST. The regulation of miR-181a on PTEN was mediated by lncRNA XIST. The proliferation and invasion of cells with siXIST were significantly enhanced compared with those of control cells, while knockdown of miR-181a abolished the enhancing effects. CONCLUSIONS: MiR-181a can promote HCC metastasis by targeting PTEN, which is regulated by lncRNA XIST.

Superhydrophobic SiO2-Glass Bubbles Composite Coating for Stable and Highly Efficient Daytime Radiative Cooling.

Energy-free radiative cooling is a green and ideal solution to replace air conditioning by reflecting sunlight spontaneously and radiating excess heat through atmospheric transparency windows to outer space for passive cooling. However, most radiative cooling materials are susceptible to contamination by dust, rain, etc., which reduces the cooling capacity in outdoor environments. Herein, we report on a superhydrophobic daytime radiative cooling coating based on SiO2-coated glass bubble (SiO2-GB) powder that achieves strong sunlight reflectivity (96%) and high mid-infrared emissivity (98%), effectively producing an ambient temperature drop of 11.1 °C in direct outdoor sunlight. More importantly, the coating has good superhydrophobic properties with a water contact angle of 157°, which allows the coating to be self-cleaning to keep the coating free from contamination and effectively maintain good radiation cooling performance. In addition, the prepared coatings remain hydrophobic and keep good radiative cooling properties when exposed to different pH solutions and long-term exposure to UV irradiation, which has important implications for sustainable applications, and our work holds great promise for the energy efficiency of building materials and their long-term outdoor service.

Structural features, selenization modification, antioxidant and anti-tumor effects of polysaccharides from alfalfa roots.

Hot water extraction and chromatographic purification methods were used to extract and purify two polysaccharides (RAPS-1 and RAPS-2) from the roots of alfalfa. Subsequently, RAPS-2 was modified using the HNO3/Na2SeO3 method to obtain Se-RAPS-2. The structural features, antioxidant and in vitro anti-tumor activities of the three polysaccharides were evaluated. The structural analysis revealed that RAPS-1 (Mw = 10.0 kDa) was composed of rhamnose, xylose, arabinose, galacturonic acid, mannose and glucose, whereas RAPS-2 (Mw = 15.8 kDa) consisted of rhamnose, xylose, galacturonic acid, mannose, glucose and galactose. RAPS-1 contained 1 â†’ 2, 1 â†’ 4, 1 â†’ 3, and 1 â†’ 6 or 1 â†’ glycosidic bonds; however, while RAPS-2 lacked 1 â†’ 4 glycosidic linkages. The molecular weight of Se-RAPS-2 was 11.0 kDa less than that of RAPS-2. The results of activities demonstrated that Se-RAPS-2 displayed superior antioxidant activity and inhibitory effect in HepG2 cells than RAPS-1 and RAPS-2.

A network pharmacology study on the triterpene saponins from Medicago sativa L. for the treatment of Neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are characterized by progressive and irreversible, is a kind of complex illnesses, and the long-term therapy which is frequently associated with adverse side effects. Medicago sativa L., widely consumed as a vegetable, has the effects of improving memory and relieving central nervous system diseases. However, there are less studies on its specific mechanism for NDDs. In this investigation, we applied a method of network pharmacology, which combined molecular docking and network analysis to decipher the mechanisms of M. sativa in NDDs. The pharmacological system generated 55 triterpene saponins from M. sativa, and predicted 27 potential targets with 100 pathways in the treatment of NDDs. As a result, 13 compounds, 10 target proteins, and 6 signaling pathways were found to play important roles in the treatment of NDDs. In addition, in vitro experiments of isolates confirmed activities for NDDs, which were consistent with the results of network pharmacology prediction. PRACTICAL APPLICATIONS: Medicago sativa L. has been widely consumed as a vegetable, which possesses many nutritional components. As a functional food stuff, M. sativa can improve human health, such as memory improving activities, relieving central nervous system diseases, immunomodulatory, antioxidant, anticancer, and anti-inflammatory. In this article, the mechanism of triterpene saponins from M. sativa against NDDs was successfully predicted by network pharmacology method. The results will serve as a reference of M. sativa against NDDs.

Modified Backtracking Search Optimization Algorithm Inspired by Simulated Annealing for Constrained Engineering Optimization Problems.

The backtracking search optimization algorithm (BSA) is a population-based evolutionary algorithm for numerical optimization problems. BSA has a powerful global exploration capacity while its local exploitation capability is relatively poor. This affects the convergence speed of the algorithm. In this paper, we propose a modified BSA inspired by simulated annealing (BSAISA) to overcome the deficiency of BSA. In the BSAISA, the amplitude control factor (F) is modified based on the Metropolis criterion in simulated annealing. The redesigned F could be adaptively decreased as the number of iterations increases and it does not introduce extra parameters. A self-adaptive ε-constrained method is used to handle the strict constraints. We compared the performance of the proposed BSAISA with BSA and other well-known algorithms when solving thirteen constrained benchmarks and five engineering design problems. The simulation results demonstrated that BSAISA is more effective than BSA and more competitive with other well-known algorithms in terms of convergence speed.

The neuroprotective and antioxidant profiles of selenium-containing polysaccharides from the fruit of Rosa laevigata.

Rosa laevigata fruit has been known as a functional foodstuff for a long time. Recently, increasing attention has been given to polysaccharides from R. laevigata fruit due to their numerous medicinal and nutritional properties. In this study, a rapid and effective approach for the extraction and separation of polysaccharides from the title fruit was developed using microwave-assisted aqueous two-phase extraction (MA-ATPE) with a PEG/ammonium sulfate system. After analysis of the response surface methodology (RSM) data based on a Box-Behnken design (BBD), a model was proposed and was found to predict an optimum yield value of 258.99 mg g-1 which is in good agreement with the experimental value (258.59 mg g-1). Two selenium (Se)-containing polysaccharides, Se-RLFP-1 and Se-RLFP-2, were isolated from R. laevigata fruit. Their chemical structures were elucidated by acid hydrolysis, weight-average molecular mass and Se-content analysis, along with UV, FT-IR, 1H and 13C NMR spectroscopy. As a result, Se-RLFP-1 was found to be mainly composed of mannose, glucose, galactose and xylose in a molar ratio of 1.4 : 7.9 : 1.0 : 1.5, while Se-RLFP-2 was composed of mannose, rhamnose, glucose, galactose and xylose (12.6 : 1.0 : 38.3 : 5.6 : 19.6). Furthermore, the antioxidant properties of the polysaccharides were investigated on the basis of FRAP, ABTS and DPPH radical scavenging assays. The results showed that the two polysaccharides had a noticeable effect on the radical scavenging of ABTS and DPPH, especially at high concentrations. In addition, the neuroprotective effect of Se-RLFP-1 and Se-RLFP-2 against oxidative stress induced by H2O2 in SH-SY5Y neuroblastoma cells was also investigated. In particular, Se-RLFP-1 exhibited obvious neuroprotective activity at a concentration of 100 µg mL-1.

Effects of the combined administration of entecavir and adefovir dipivoxil to improve hepatic fibrosis in hepatitis B patients with interferon resistance.

BACKGROUND: To observe the effect of the combined administration of entecavir and adefovir dipivoxil to improve hepatic fibrosis in hepatitis B patients with interferon resistance. METHODS: This study comprised 90 hepatitis B patients with hepatic fibrosis and interferon (IFN) resistance who were admitted in the hospital's department of infectious disease for diagnosis and treatment between January 2013 and September 2015. They were randomly divided into two groups in accordance with the random number table: the combination treatment group (N.=45) and the entecavir group (N.=45). They were observed for any variations in the indexes of liver function and fibrosis, as well as the Model for end-stage liver disease (MELD) scores, before and after treatment. RESULTS: After treatment, the levels of the indexes in both groups (the combination treatment group vs. the entecavir group) were as follows: bilirubin (67.5±7.7 vs. 82.4±13.5 µmol/L); International Normalized Ratio (INR) (1.21±0.8 vs. 1.14±0.7); creatinine (147.3±12.4 vs. 287.4±21.6 mg/dL); GGT (67.4±23.2 vs. 88.4±23.7 U/L); and ALT (63.4±40.8 vs. 96.5±23.5 U/L). In comparison of the indexes of hepatic fibrosis between the two groups, we found the following differences: PCIII (67.5±7.7 vs. 82.4±13.5 µg/L); IV-C (61.3±18.7 vs. 74.5±17.9 µg/L); HA (147.3±12.4 vs. 87.4±31.6 µg/L); and LN (88.7±13.2 vs 102.5±23.4 µg/L). The results showed that the differences in comparison of the indexes before and after the treatment were statistically significant (P<0.05). After treatment, the MELD score of patients in the combination treatment group was significantly lower than that in the entecavir group (18.7±3.2 vs. 22.5±3.4), with a statistically significant difference (P<0.05). CONCLUSIONS: In the chronic hepatitis B patients with interferon resistance, the combined administration of entecavir and adefovir dipivoxil can significantly improve liver function, hepatic fibrosis and MELD scores. The results highlight the need to promote the benefits of this drug combination in helping chronic hepatitis B patients with interferon resistance, and to promote its application in clinical practices.