Regulation Of Energy Metabolism Research Articles

Sirtuin 3 drives sex-specific responses to age-related changes in mouse embryonic fibroblasts

The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process.

Combined transcriptomic and metabolomic analysis of the mechanism by which Bacillus velezensis induces resistance to anthracnose in walnut

Walnut (Juglans spp.), a significant deciduous tree of economic and ecological importance, faces substantial threats from walnut anthracnose, primarily caused by Colletotrichum gloeosporioides. Bacillus velezensis has shown promise in mitigating this fungal pathogen. To delve deeper into the induction mechanism of B. velezensis on walnut plant resistance, we conducted a metabolomic analysis on walnut leaves from six different treatment groups. Specifically, the groups were defined as follows: Group B.v. was inoculated with B. velezensis alone, Group CK served as the blank control, and Group C.g. was inoculated solely with C. gloeosporioides. Group B.v.−C.g. received B. velezensis followed by C. gloeosporioides inoculation. Group B.v.+C.g. underwent simultaneous inoculation with both B. velezensis and C. gloeosporioides, while Group C.g.−B.v. was treated first with C. gloeosporioides then B. velezensis. A total of 1,503 metabolites were detected, mainly including flavonoids, terpenoids, and steroids. The results revealed that B. velezensis spraying not only enhanced the inherent resistance of walnut plants but also significantly regulated walnut plants already infected with C. gloeosporioides. This was mainly achieved by inducing walnut plants to adjust their metabolic pathways such as salicylic acid, jasmonic acid, and abscisic acid, thereby strengthening their stress response. Transcriptomic and metabolomic correlation analyses showed that in the comparisons of B.v. vs. CK, C.g. vs. CK, and C.g.−B.v. vs. C.g., 59, 244, and 122 differential abundance metabolites were detected, along with 7860, 3677, and 5587 differential genes, respectively. Amino acid synthesis, starch and sucrose metabolism, photosynthesis, phenylpropane metabolism, purine metabolism, and glutathione metabolism played crucial roles in walnut’s disease resistance mechanism. Further analysis revealed that B. velezensis induced walnut plants to regulate multiple genes, such as LOC109005403, LOC108985444 and LOC118344177, resulting in the production of defensive metabolites such as palmitic acid, coumarin and ferulic acid, thereby enhancing their resistance to C. gloeosporioides. In summary, B. velezensis induces systemic resistance in walnut plants by modulating the metabolic pathways of salicylic acid, jasmonic acid, and abscisic acid. It enhances this resistance by strengthening cell walls, synthesizing defensive secondary metabolites, and regulating energy metabolism and stress responses. These findings provide a solid theoretical foundation for the future field application of B. velezensis in controlling walnut anthracnose.

Histone-like transcription factor Hfl1p in Candida albicans harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development

ABSTRACT Candida albicans is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p’s diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the hfl1Δ/hfl1Δ mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p’s critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of C. albicans’ metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in C. albicans.

Mitochondria in tumor immune surveillance and tumor therapies targeting mitochondria.

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

The effects of sodium-glucose cotransporter 2 inhibitors on the 'forgotten' right ventricle.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation.

Patients with lung adenocarcinoma (LUAD) generally have poor prognosis. Abnormal cellular energy metabolism is a hallmark of LUAD. Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) is a member of the γ-glutamylcyclotransferase family and an unfolded protein response pathway regulatory gene. Its biological function and molecular regulatory mechanism, especially regarding energy metabolism underlying LUAD, remain unclear. By utilizing tissue microarray and data from The Cancer Genome Atlas and Gene Expression Omnibus, we found that CHAC1 expression was markedly higher in LUAD tissues than in non-tumor tissues, and was positively correlated with poor prognosis. Phenotypically, CHAC1 overexpression enhanced the proliferation, migration, invasion, tumor sphere formation, and glycolysis ability of LUAD cells, resulting in tumor growth both in vitro and in vivo. Mechanistically, through a shotgun mass spectrometry-based proteomic approach and high-throughput RNA sequencing, we found that CHAC1 acted as a bridge connecting UBA2 and PKM2, enhancing the SUMOylation of PKM2. The SUMOylated PKM2 then transferred from the cytoplasm to the nucleus, activating the expression of glycolysis-related genes and enhancing the Warburg effect. Lastly, E2F Transcription Factor 1 potently activated CHAC1 transcription by directly binding to the CHAC1 promoter in LUAD cells. The results of this study implied that CHAC1 regulates energy metabolism and promotes glycolysis in LUAD progression.

The new function of FaSRT2-1 protein in energy metabolism: Promoting strawberry fruit quality and ripening

Sirtuins (SRTs) are nicotinamide adenine dinucleotide (NAD+) dependent II histone deacetylases (HDACs) that have been understudied in horticultural crops. However, their functions in regulating mitochondrial energy metabolism and influencing fruit development and quality formation remain unclear. In this study, we found that FaSRT2–1 exhibits diverse subcellular localizations. Overexpression of FaSRT2–1 promoted strawberry fruit quality formation (soluble sugars, organic acids, anthocyanins) and accelerated ripening. Conversely, knockout of FaSRT2–1 yielded opposite results. During fruit ripening, ATP content and ATP/ADP ratio gradually increased, and FaSRT2–1 promoted ATP accumulation and decreased before and after the deep red stage, respectively, indicating its role in fruit ripening and senescence. FaSRT2–1 interacted with energy-related proteins (FaRPT4a, FaATPβ and FaATPγ) to increase ATP content and the ATP/ADP ratio. Additionally, FaSRT2–1 collaborated with FaGDH2 and FaWDR5B to increase the accumulation of soluble sugars, organic acids and anthocyanins. Meanwhile, FaRPT4a, FaATPγ, FaGDH2 and FaWDR5B were co-localized with FaSRT2–1, while FaATPβ was localized in both the cytoplasm and mitochondria. Transient overexpression experiments further highlight the roles of FaRPT4a and FaGDH2/FaWDR5B in modulating ATP accumulation and fruit ripening, respectively. In summary, FaSRT2–1 plays important roles in promoting strawberry fruit ripening, senescence and quality formation by regulating energy metabolism.

Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.

Lipid droplets (LDs) are dynamic storage organelles with central roles in lipid and energy metabolism. They consist of a core of neutral lipids, such as triacylglycerol, which is surrounded by a monolayer of phospholipids and specialized surface proteins. The surface composition determines many of the LD properties, such as size, subcellular distribution, and interaction with partner organelles. Considering the diverse energetic and metabolic demands of various cell types, it is not surprising that LDs are highly heterogeneous within and between cell types. Despite their diversity, all LDs share a common biogenesis mechanism. However, adipocytes have evolved specific adaptations of these basic mechanisms, enabling the regulation of lipid and energy metabolism at both the cellular and organismal levels. Here, we discuss recent advances in the understanding of both the general mechanisms of LD biogenesis and the adipocyte-specific adaptations controlling these fascinating organelles.

Integrating network pharmacology and transcriptomics to study the potential mechanism of Jingzhi Niuhuang Jiedu tablet in rats with accumulation of heat in the lungs and stomach

Accumulation of heat in the lungs and stomach (AHLS) is an important syndrome within the realm of traditional Chinese medicine (TCM). It is the fundamental reason behind numerous illnesses, including mouth ulcers, dermatological conditions, acne, and pharyngitis. Jingzhi Niuhuang Jiedu tablet (JN) serves as the representative prescription for treatment of AHLS clinically. However, the effective components and mechanism of JN's impact on AHLS remain unexplored. The objective of this research was to analyze the effective components of JN and investigate the therapeutic effect and potential mechanism of JN on AHLS. The effective compounds of JN extract were analyzed and identified using UHPLC-Q-Exactive/HRMS. Utilizing network pharmacology to investigate JN's multi-target, multi-pathway process in treating AHLS. Subsequently, anti-inflammatory activities of JN extract were evaluated in the RAW264.7cells stimulated by lipopolysaccharide (LPS). In addition, a rat AHLS model induced by LPS and dried ginger was established. Pathological changes in rat lung and stomach tissues observed by HE staining and Masson's trichrome staining. Additionally, the expression of TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid (BALF) was identified through the ELISA assay. For a deeper understanding of how JN might affect AHLS, transcriptomics was utilized to examine differential genes and their underlying mechanisms. Concurrently, techniques like quantitative polymerase chain reaction (q-PCR), immunofluorescence, and western blotting (WB) were employed to confirm various mRNA and protein expression, including Il17ra, Il17re, IL-17A, IL-1β, IL-6, PPARγ, PGC1-α and UCP1. We identified 178 potential effective components in the JN extract. Network pharmacology analysis showed that the 144 components in JN act on 200 key targets for the treatment of AHLS by suppressing inflammation, regulating energy metabolism, and gastric function. In addition, JN suppressed the LPS-stimulated generation of NO, TNF-α, IL-1β, and IL-6 in RAW264.7cells. And JN treatment effectively alleviated lung and stomach injury and reduced inflammation in rats. Analysis of RNA-seq from lung tissues revealed JN's substantial control over crucial genes in the IL-17 signaling pathway, including Il1b and Il17ra. Likewise, RNA sequencing of stomach tissues revealed that JN markedly decreased crucial genes in the Thermogenesis pathway, including Ppargc1a and Ppara. Additional experimental findings confirmed that treatment with JN significantly reduced the expression levels of mRNA (Il17ra, Il17re, Il1b, Ppargc1a and Ucp1), and the expression levels of protein (IL-17A, IL-1β, IL-6, PPARγ, PGC1-α and UCP1). This study not only analyzes the effective components of JN but also reveals that JN could effectively ameliorate AHLS by inhibiting IL-17 signaling pathway and Thermogenesis pathway, which provides evidence for subsequent clinical studies and drug development.

Effect of Substituting of Amino Acids Residues Ser-911 and Thr-912 in the Plasma Membrane H+-ATPase of Yeast <i>Saccharomyces cerevisiae</i> on Its Activity and Distribution of Polyphosphates

The vital enzyme of yeast metabolism, plasma membrane H+-ATPase (PMA1), is phosphorylated during folding and functioning. The main phosphorylation sites are Ser911 and Thr-912 in the C-terminal regulatory domain. The work used wild and mutant forms of the enzyme with substitutions of these amino acid residues with Ala or Asp to determine their role in the functioning of the ATPase and the distribution of polyphosphates (polyP) by fractions. Growth parameters, ATP content, and in situ polyP distribution were determined on whole cells. To determine the ATPase activity in vitro, plasma membranes containing wild-type enzyme and mutant forms were isolated. Mutants S911D, T912D and S911D/T912A had ATPase activity close to the wild type; mutant S911A had increased activity. The growth rate of strains S911D, T912D and S911D/T912A was 2.0‒3.0 times lower than that of the wild type, and the growth rate of S911A was close to the wild type. Mutations S911D and S911D/T912A caused a decrease in ATP content by 2.0‒2.5 times. All substitutions affected the distribution of polyP by fractions. The effect depended on the chemical nature of the substitution: in the case of replacement with Asp, which changes the type of phosphosite, there was a decrease in the polyR1 fraction and an increase in the polyR2 fraction; when replaced with Ala, which removes phosphosite, the effect was the opposite. The content of the polyP3 fraction increased in all mutants. The data indicate that the residues of Ser911 and Thr-912 are important not only for the normal functioning of the PMA of H+-ATPase, but also for the regulation of phosphorus and energy metabolism.

Regulation of glucose and energy metabolism through actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.

There are several physiological and pharmacological actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide for the regulation of blood glucose and bodyweight.

Effects of Selenium, Iron, and Zinc Enrichment on Cultured Sea Cucumber (Apostichopus Japonicus).

Selenium, iron, and zinc (Se, Fe, Zn) are essential trace elements crucial for animal growth, development, and immune protection, but they can be detrimental in excess. This study evaluates the impacts of Se, Fe and Zn on Apostichopus japonicus over a period of nine days, utilizing concentrations ranging from low to high: Se (0.20 µmol/L and 0.82 µmol/L), Fe (4.74 µmol/L and 18.96 µmol/L), Zn (1.88 µmol/L and 7.51 µmol/L). Concentrations of these trace elements in sea cucumbers increased with exposure time. Activities of CAT, SOD, and GSH-PX enzymes were enhanced. Transcriptomic analyses of sea cucumber body wall revealed significant gene expression changes, with differentially expressed genes (DEGs) numbering 294 at high and 945 at low Se concentrations, 906 at high and 210 at low Fe concentrations, and 423 at high and 123 at low Zn concentrations. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses highlighted DEGs enrichment in critical metabolic and immune-related pathways, including DNA replication, arachidonic acid metabolism, and oxidative phosphorylation. These results suggest that energy metabolism and immune regulation are pivotal in managing these elements, potentially enhancing sea cucumber immunity. This study enhances our comprehension of the physiological responses of sea cucumbers to trace elements and provides a theoretical basis for their use in aquaculture.

Temporal and tissue-specific regulation of energy metabolism in the swimming crab Portunus trituberculatus during nitrite stress and recovery

Nitrite is a common pollutant in aquaculture systems that poses a significant threat to aquatic animals. Energy metabolism is critical in ensuring survival of animals under environmental stressors. However, regulation of energy metabolism in crustaceans under nitrite stress has not been well understood. Here we investigated energy metabolism regulation during nitrite stress and recovery in different tissues of the swimming crab Portunus trituberculatus, an important aquaculture species in China. Our results revealed that nitrite can cause tissue hypoxia and impair energy homeostasis, and energy balance cannot be restored even after a 96-hour recovery. Following exposure, mobilization of glycogen and lipids exhibited different temporal patterns. In response to energy imbalance, AMPK signaling was activated to counter energy imbalance. However, prolonged nitrite stress impaired AMPK signaling, leading to a further decline in energy supply. The findings improve our understanding for nitrite toxicity in P. trituberculatus, and provide valuable information for aquaculture management.

Two-Pronged Attack: Dual Activation of Fat Reduction Using Near-Infrared-Responsive Nanosandwich for Targeted Anti-Obesity Treatment.

Excessive fat accumulation and chronic inflammation are two typical characteristics of obesity. AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, is involved in adipogenesis, lipogenesis, and inflammation modulation in adipose tissue (AT). Thus, effective lipid reduction and anti-inflammation through AMPK regulation play vital roles in treating obesity. Herein, an anti-obesity nanosandwich is fabricated through attaching polymetformin (PolyMet) onto photothermal agent black phosphorus nanosheets (BP). PolyMet activates AMPK to inhibit adipogenesis, promote browning, and mitigate AT inflammation by decreasing macrophage infiltration, repolarizing macrophage phenotype, and downregulating pro-inflammatory cytokines. Additionally, BP induces lipolysis and apoptosis of adipocytes and macrophages through a photothermal effect. By further functionalization using hyaluronic acid (HA) and MMP2 substrate-linking P3 peptide-modified HA (P3-HA), an enhanced anti-obesity effect is obtained by dual-targeting of P3 and HA, and HA-mediated CD44 poly-clustering after MMP2 cleavage. Upon laser irradiation, the designed nanosandwich (P3-HA/PM@BP) effectively inhibits obesity development in obese mice, increases M2/M1 ratio in AT, reduces the serum levels of cholesterol/triglyceride and improves insulin sensitivity, exhibiting promising research potential to facilitate the clinical development of modern anti-obesity therapies.

STING regulates aging-related osteoporosis by mediating the Hk2-Vdac1 mitochondrial axis

Metabolic abnormalities and mild inflammation are hallmarks of aging and major driving factors for aging-related damage and bone metabolic diseases. Mitochondria are crucial links in energy metabolism and immune homeostasis regulation. Mitochondrial dysfunction is considered one of the pathogenic factors of aging-related osteoporosis, but its mechanism of action needs further research. Here, we demonstrated that the interaction between stimulator of interferon genes (STING)-mediated regulation of hexokinase 2 (Hk2)-voltage-dependent anion channel-1 (Vdac1) is a critical factor contributing to mitochondrial dysfunction and osteogenic abnormalities during aging. As the aging process progresses, factors related to aging cause an increase in STING expression, which disrupts the interaction between Hk2 and Vdac1. Dissociation of Hk2 from Vadc1 triggered the opening of the mitochondrial inner mitochondrial permeability transition pore (mPTP), leading to mitochondrial dysfunction and abnormal osteogenic differentiation, thereby disrupting bone homeostasis. In brief, this study demonstrates that STING acts as an intracellular metabolic Checkpoint, influencing mitochondrial function to promote the development of osteoporosis. These findings significantly enhance the development of STING-targeted treatments for aging-related osteoporosis.

Investigating the Impact of Fasting and Refeeding on Blood Biochemical Indicators and Transcriptional Profiles in the Hypothalamus and Subcutaneous Adipose Tissue in Geese.

Fasting and refeeding systems can cause significant short-term fluctuations in nutrient and energy levels, triggering adaptive physiological responses in animals. This study examines the effects of fasting and refeeding on blood biochemical indicators and transcriptional profiles in the hypothalamus and subcutaneous adipose tissue of geese. Biochemical assays reveal that fasting significantly increases levels of free fatty acids and glucagon, while reducing concentrations of triglycerides, leptin, and insulin. Transcriptomic analyses identify a complex transcriptional response in both the hypothalamus and subcutaneous adipose tissue, affecting several metabolic pathways and key genes associated with feed intake and energy metabolism. In subcutaneous adipose tissue, fasting downregulates genes involved in fatty acid synthesis (LPL, SCD, and ACSL1) and upregulates PLIN2, a gene promoting lipid droplet degradation. Fasting affects a variety of metabolic pathways and critical genes in the hypothalamus, including Apelin, insulin, and mTOR signaling pathways. After fasting, the mRNA expression of NOG, GABRD, and IGFBP-1 genes in the hypothalamus are significantly upregulated, while proopiomelanocortin (POMC) gene expression is markedly downregulated. This study highlights the intricate biological responses to nutritional changes in geese, which adds to our understanding of energy balance and metabolic regulation in avian species.

Unraveling the role of lactate-related genes in myocardial infarction

BackgroundLactate is a crucial intermediary, facilitating communication between myocardial energy metabolism and microenvironmental regulation. The present study aimed to investigate the relationship between lactate-related genes (LRGs) and myocardial infarction (MI). MethodsA total of 23 LRGs exhibited differential expression between individuals with MI and healthy controls. Lasso regression analysis and validation with the GSE61144 dataset identified three hub genes: COX20, AGK, and PDHX. Single-gene GSEA of these genes revealed strong enrichment in pathways related to amino acid metabolism, cell cycle, and immune functions. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was utilized to validate the expression levels of the hub genes. ResultsImmune infiltration analysis revealed differences in CD4+ T and CD8+ T cells between the MI and control groups. Additionally, 67 candidate drugs targeting the three hub LRGs were identified, and a ceRNA network was constructed to explore the intricate interactions among these genes. ConclusionsThese findings enhance the understanding of MI and have potential therapeutic implications.

Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases.

Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs.

The tumor suppressor Parkin exerts anticancer effects through regulating mitochondrial GAPDH activity.

Cancer cells preferentially utilize glycolysis for energy production, and GAPDH is a critical enzyme in glycolysis. Parkin is a tumor suppressor and a key protein involved in mitophagy regulation. However, the tumor suppression mechanism of Parkin has still not been elucidated. In this study, we identified mitochondrial GAPDH as a new substrate of the E3 ubiquitin ligase Parkin, which mediated GAPDH ubiquitination in human cervical cancer. The translocation of GAPDH into mitochondria was driven by the PINK1 kinase, and either PINK1 or GAPDH mutation prevented the accumulation of GAPDH in mitochondria. Parkin caused the ubiquitination of GAPDH at multiple sites (K186, K215, and K219) located within the enzyme-catalyzed binding domain of the GAPDH protein. GAPDH ubiquitination was required for mitophagy, and stimulation of mitophagy suppressed cervical cancer cell growth, indicating that mitophagy serves as a type of cell death. Mechanistically, PHB2 served as a key mediator in GAPDH ubiquitination-induced mitophagy through stabilizing PINK1 protein and GAPDH mutation resulted in the reduced distribution of PHB2 in mitophagic vacuole. In addition, ubiquitination of GAPDH decreased its phosphorylation level and enzyme activity and inhibited the glycolytic pathway in cervical cancer cells. The results of in vivo experiments also showed that the GAPDH mutation increased glycolysis in cervical cancer cells and accelerated tumorigenesis. Thus, we concluded that Parkin may exert its anticancer function by ubiquitinating GAPDH in mitochondria. Taken together, our study further clarified the molecular mechanism of tumor suppression by Parkin through the regulation of energy metabolism, which provides an experimental basis for the development of new drugs for the treatment of human cervical cancer.

Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis

Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.