SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense

Abstract Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose‐6‐phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation

WT1 Recruits TET2 to Regulate Its Target Gene Expression and Suppress Leukemia Cell Proliferation

The TET2 DNA dioxygenase regulates cell identity and suppresses tumorigenesis by modulating DNA methylation and expression of a large number of genes. How TET2, like most other chromatin modifying enzymes, is recruited to specific genomic sites is unknown. Here we report that WT1, a sequence-specific transcription factor, is mutated in a mutually exclusive manner with TET2, IDH1 and IDH2 in acute myeloid leukemia (AML). WT1 physically interacts with and recruits TET2 to its target genes to activate their expression. The interaction between WT1 and TET2 is disrupted by multiple AML-derived TET2 mutations. TET2 suppresses leukemia cell proliferation and colony formation in a manner dependent on WT1. These results provide a mechanism for targeting TET2 to specific DNA sequence in the genome. Our results also provide an explanation for the mutual exclusivity of WT1 and TET2 mutations in AML and suggest an IDH1/2-TET2-WT1 pathway in suppressing AML

Optimal Operation of Interprovincial Hydropower System Including Xiluodu and Local Plants in Multiple Recipient Regions

This paper focuses on the monthly operations of an interprovincial hydropower system (IHS) connected by ultrahigh voltage direct current lines. The IHS consists of the Xiluodu Hydropower Project, which ranks second in China, and local plants in multiple recipient regions. It simultaneously provides electricity for Zhejiang and Guangdong provinces and thus meets their complex operation requirements. This paper develops a multi-objective optimization model of maximizing the minimum of total hydropower generation for each provincial power grid while considering network security constraints, electricity contracts, and plant constraints. The purpose is to enhance the minimum power in dry season by using the differences in hydrology and regulating storage of multiple rivers. The TOPSIS method is utilized to handle this multi-objective optimization, where the complex minimax objective function is transformed into a group of easily solved linear formulations. Nonlinearities of the hydropower system are approximatively described as polynomial formulations. The model was used to solve the problem using mixed integer nonlinear programming that is based on the branch-and-bound technique. The proposed method was applied to the monthly generation scheduling of the IHS. Compared to the conventional method, both the total electricity for Guangdong Power Grid and Zhejiang Power Grid during dry season increased by 6% and 4%, respectively. The minimum monthly power also showed a significant increase of 40% and 31%. It was demonstrated that the hydrological differences between Xiluodu Plant and local hydropower plants in receiving power grids can be fully used to improve monthly hydropower generation

Efficacy and safety of microwave ablation for benign breast lesions: a systematic review and meta-analysis

AIM: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of microwave ablation (MWA) for benign breast lesions. MATERIAL AND METHODS: PubMed, Embase, Web of Science, Cochrane Library databases, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform databases were searched. RESULTS: A total of 10 studies were included, giving a sample size of 1241 patients and 2729 benign breast lesions. The first complete ablation success rate was 96%. The volume reduction ratio (VRR) after 3/6/12 months was 47.4%, 62.1%, and 85.8%, respectively. After 12 months, the lesion disappearance rate was 53.6%, and the efficiency rate was 99%. The rate of excellent cosmesis was 88% and the rate of good cosmesis was 10%. The complication rate was 2%. CONCLUSIONS: MWA is safe and effective for treating benign breast lesions. It can be a promising minimally invasive choice for benign breast lesions

ORTHOGONAL EXPERIMENTAL STUDY OF BASALT-POLYVINYL ALCOHOL FIBER REINFORCED CONCRETE

Hybrid fiber reinforced concrete possessing both strength and durability was developed using the orthogonal test method. Various factors' effects on the fundamental properties of hybrid fiber-reinforced concrete were investigated. The results indicate that the water-binder ratio significantly influences compressive strength. Both the basalt fiber content and polyvinyl alcohol fiber content significantly impact fluidity. Both water-binder ratio and polyvinyl alcohol fiber content significantly affect electric flux, which decreases with increasing fly ash content. The hybrid fiber-reinforced concrete underwent comparison and evaluation via range analysis and variance analysis, culminating in the determination of the optimal concrete mix ratio using the efficiency coefficient method. This concrete exhibits superior strength and enhanced resistance to chloride penetration, making it more suitable for harsh environments

Arabidopsis DELLA protein degradation is controlled by a type-one protein phosphatase, TOPP4.

Gibberellins (GAs) are a class of important phytohormones regulating a variety of physiological processes during normal plant growth and development. One of the major events during GA-mediated growth is the degradation of DELLA proteins, key negative regulators of GA signaling pathway. The stability of DELLA proteins is thought to be controlled by protein phosphorylation and dephosphorylation. Up to date, no phosphatase involved in this process has been identified. We have identified a dwarfed dominant-negative Arabidopsis mutant, named topp4-1. Reduced expression of TOPP4 using an artificial microRNA strategy also resulted in a dwarfed phenotype. Genetic and biochemical analyses indicated that TOPP4 regulates GA signal transduction mainly via promoting DELLA protein degradation. The severely dwarfed topp4-1 phenotypes were partially rescued by the DELLA deficient mutants rga-t2 and gai-t6, suggesting that the DELLA proteins RGA and GAI are required for the biological function of TOPP4. Both RGA and GAI were greatly accumulated in topp4-1 but significantly decreased in 35S-TOPP4 transgenic plants compared to wild-type plants. Further analyses demonstrated that TOPP4 is able to directly bind and dephosphorylate RGA and GAI, confirming that the TOPP4-controlled phosphorylation status of DELLAs is associated with their stability. These studies provide direct evidence for a crucial role of protein dephosphorylation mediated by TOPP4 in the GA signaling pathway

Correction: Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1.

[This corrects the article DOI: 10.1371/journal.pbio.1002243.]

Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1.

Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation

Loss-of-function mutants <i>rga-t2</i> and <i>gai-t6</i> can partially suppress the dwarfed phenotype of <i>topp4-1</i>.

<p>(<b>A</b>) Representative 5-week-old wild-type, <i>topp4-1</i>, <i>rga-t2</i>, <i>rga-t2 topp4-1</i>, <i>gai-t6</i>, <i>gai-t6 topp4-1</i>, <i>rga-t2 gai-t6</i>, and <i>rga-t2 gai-t6 topp4-1</i> plants. The <i>rga-t2 topp4-1</i>, <i>gai-t6 topp4-1</i>, and <i>rga-t2 gai-t6 topp4-1</i> double and triple mutants were back-crossed with Col six times. The <i>rga-t2</i>, <i>gai-t6</i> single mutants and the <i>rga-t2 gai-t6</i> double mutant screened from the same genetic cross were used as control. Scale bars = 1 cm. (<b>B</b>) The height of 6-week-old wild-type, <i>rga-t2</i>, <i>gai-t6</i>, <i>rga-t2 gai-t6</i>, <i>topp4-1</i>, <i>rga-t2 topp4-1</i>, <i>gai-t6 topp4-1</i>, and <i>rga-t2 gai-t6 topp4-1</i> plants. Asterisk represents statistic differences based on Student's <i>t</i> test with P<0.05. Error bars represent SE (n = 20).</p