Mitochondrial Energy Metabolism Research Articles

Lesion-localized hydrogels functionalized with engineered extracellular matrix restore cellular homeostasis by enhancing mitochondrial energy metabolism for osteoarthritis therapy

Cartilage damage and degeneration are fundamental pathological features of osteoarthritis (OA), attributed largely to disruptions in chondrocyte homeostasis. Tissue engineering employing functional bioactive materials presents a promising avenue for cartilage regeneration and repair. Particularly, extracellular matrix (ECM) produced by mesenchymal stem cells (MSCs) is gaining traction in the field of tissue engineering and scaffold-based regenerative therapies due to its robust bioactivity and excellent biocompatibility. In this study, we utilized specific inflammatory cytokines associated with OA as stimulators to optimize the MSC-derived secretome. Our in vitro experiments demonstrated that the engineered ECM effectively inhibited early chondrocyte apoptosis, reversed cellular senescence, and maintained anabolic-catabolic equilibrium. Moreover, we developed aldehyde- and methacrylic anhydride-modified hyaluronic acid hydrogels incorporated with ECM (ECM@AH) using photo-cross-linking techniques. The affinity of these ECM-functionalized hydrogels for degraded cartilage was confirmed through in situ cartilage lesion localization experiments in the knee joints of rat OA models. Further in vitro analysis revealed that the engineered ECM@AH, especially IFN-γ-ECM@AH, sustains chondrocyte homeostasis by restoring mitochondrial energy metabolism. Animal studies demonstrated that ECM@AH, localized to cartilage lesions, could reverse cartilage matrix degradation and promote cartilage repair, underscoring the potential of this biomaterial in OA treatment.

The dual-edged role of SIRT1 in energy metabolism and cardiovascular disease.

Regulation of energy metabolism is pivotal in the development of cardiovascular diseases. Dysregulation in mitochondrial fatty acid oxidation (FAO) has been linked to cardiac lipid accumulation and diabetic cardiomyopathy. Sirtuin 1 (SIRT1) is a deacetylase that regulates the acetylation of various proteins involved in mitochondrial energy metabolism. SIRT1 mediates energy metabolism by directly and indirectly affecting multiple aspects of mitochondrial processes, such as mitochondrial biogenesis. SIRT1 interacts with essential mitochondrial energy regulators such as Peroxisome Proliferator-Activated Receptor α (PPARα), PPARgcoactivator-1 (PGC1α), Estrogen-Related Receptor α (ERRα), and their downstream targets. Apart from that, SIRT1 regulates additional proteins, including Forkhead Box Protein O1 (FOXO1) and AMP-Activated Protein Kinase (AMPK) in cardiac disease. Interestingly, studies have also shown that the expression of SIRT1 plays a dual-edged role in energy metabolism. Depending on the physiological state, SIRT1 expression can be detrimental or protective. This review focuses on the molecular pathways through which SIRT1 regulates energy metabolism in cardiovascular diseases. We will review SIRT1 and discuss its role in cardiac energy metabolism and its benefits and detrimental effects in heart disease.

169 Vitamin and mineral supplementation to gestating beef heifers: Fetal physiology and metabolic programming

Abstract Vitamins and minerals have key roles in hormone production and action, enzyme activity, tissue synthesis, oxygen transport, and energy production. These micronutrients are efficiently transferred from the dam to the fetus during gestation to be partitioned for metabolic use and stored as postnatal mineral reserves. Maternal nutrient intake is one of the main factors that influence the availability of vitamins and minerals to the fetus. Thus, an inadequate supply of these critical nutrients can have a long-lasting impact on offspring growth and health. Evidence suggests that biological processes regulating normal growth, development, and nutrient utilization are programmed in utero, even during the earliest developmental stages. Therefore, there is a critical need to evaluate the effects of micronutrient supplementation during gestation on fetal physiology and metabolic programming. Our research group has developed research models examining the impact of maternal vitamin and mineral supplementation (VTM, supplemented vs. NoVTM, not supplemented) during the periconceptual period or throughout gestation in beef heifers. A metabolomic analysis revealed that metabolites in the oxidative phosphorylation pathway were more abundant in the liver of fetuses from VTM than NoVTM dams, suggesting that a greater supply of micronutrients during the periconceptual period and first trimester of pregnancy may positively modulate mitochondrial energy metabolism in offspring. These changes in the abundance of metabolites suggested physiological adaptations to meet fetal metabolic needs. Further, high-resolution respirometry analysis revealed greater efficiency of energy utilization in small intestinal samples of neonatal calves from VTM dams. In fact, VTM offspring were heavier from weaning to breeding phase than NoVTM offspring, suggesting that maternal nutrition affects physiological mechanisms in utero that modulate offspring energetics and efficiency of nutrient utilization in the postnatal period. Furthermore, we reported increased concentrations of histidine, aspartate, and 12 out of 14 neutral amino acids in the allantoic fluid of VTM-supplemented dams. Finally, genes involved with amino acid transport in fetal liver were upregulated in response to VTM supplementation, highlighting the intricate relationship between maternal and fetal nutrition. Vitamin and mineral supplementation were also associated with changes in gene expression, biological processes and pathways in placental tissue at d 83 of gestation. We observed an upregulation of genes in the calcium signaling and cyclic guanosine monophosphate (CGMP)-PKG signaling pathways in response to micronutrient supplementation. Calcium-mediated systems may modulate cell proliferation and steroidogenic activity in bovine placentomes, while CGMP-PKG plays a key role in vascular homeostasis. Placental blood vessel vascularity at term was indeed increased in heifers supplemented throughout gestation, emphasizing the importance of micronutrient supplementation beyond early pregnancy. Altogether, our findings suggest that vitamin and mineral supplementation in the periconceptual period and during gestation play a pivotal role in fetal metabolic programming with consequences extending to the postnatal period.

Korean Red Ginseng Extract Powder Mitigates Fasting And Postprandial Hyperglycemia in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age.

Exercise training can significantly improve skeletal muscle mitochondrial function and has been proven to be highly relevant to alterations in skeletal muscle DNA methylation. However, it remains unclear whether late-in-life exercise has an effect on promoter methylation of PGC-1α, a key regulator of mitochondrial biogenesis. Here we employed two distinct exercise modalities, constant medium intensity exercise training (CMIT) and high-intensity interval exercise training (HIIT), to investigate their impacts on PGC-1α expression and methylation regulation in skeletal muscle of aged mice. The results revealed a notable decrease in PGC-1α expression in skeletal muscle of aged mice, accompanied by elevated methylation levels of the PGC-1α promoter, and increased DNA methyltransferase (DNMT) protein expressions. However, both forms of exercise training significantly corrected PGC-1α epigenetic changes, increased PGC-1α expression, and ameliorated skeletal muscle reduction. Furthermore, exercise training led to elevated expression of proteins related to mitochondrial biogenesis and energy metabolism in skeletal muscle, improving mitochondrial structure and function. In conclusion, late-in-life exercise improved skeletal muscle function, morphology, and mitochondria biogenesis, which may be associated with hypomethylation in promoters of PGC-1α and increased content of skeletal muscle PGC-1α. Notably, there was no clear difference between HIIT and CMIT in PGC-1α expression and skeletal muscle function.

Acid sphingomyelinase inhibition induces cerebral angiogenesis post-ischemia/reperfusion in an oxidative stress-dependent way and promotes endothelial survival by regulating mitochondrial metabolism

Acid sphingomyelinase (ASM) inhibitors are widely used for the treatment of post-stroke depression. They promote neurological recovery in animal stroke models via neurorestorative effects. In a previous study, we found that antidepressants including amitriptyline, fluoxetine, and desipramine increase cerebral angiogenesis post-ischemia/reperfusion (I/R) in an ASM-dependent way. To elucidate the underlying mechanisms, we investigated the effects of the functional ASM inhibitor amitriptyline in two models of I/R injury, that is, in human cerebral microvascular endothelial hCMEC/D3 cells exposed to oxygen-glucose deprivation and in mice exposed to middle cerebral artery occlusion (MCAO). In addition to our earlier studies, we now show that amitriptyline increased mitochondrial reactive oxygen species (ROS) formation in hCMEC/D3 cells and increased ROS formation in the vascular compartment of MCAO mice. ROS formation was instrumental for amitriptyline’s angiogenic effects. ROS formation did not result in excessive endothelial injury. Instead, amitriptyline induced a profound metabolic reprogramming of endothelial cells that comprised reduced endothelial proliferation, reduced mitochondrial energy metabolism, reduced endoplasmic reticulum stress, increased autophagy/mitophagy, stimulation of antioxidant responses and inhibition of apoptotic cell death. Specifically, the antioxidant heme oxygenase-1, which was upregulated by amitriptyline, mediated amitriptyline’s angiogenic effects. Thus, heme oxygenase-1 knockdown severely compromised angiogenesis and abolished amitriptyline’s angiogenic responses. Our data demonstrate that ASM inhibition reregulates a complex network of metabolic and mitochondrial responses post-I/R that contribute to cerebral angiogenesis without compromising endothelial survival.

Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4-Induced Ferroptosis and Mitigating Mitochondrial Dysfunction.

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidationwhile promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

Imatinib therapy of chronic myeloid leukemia significantly reduces carnitine cell intake, resulting in adverse events

ObjectiveA prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells. MethodsHTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer. ResultsThis work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model. ConclusionsThis preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.

Acrolein exposure affects ovarian function by interfering with glycolysis and mitochondrial energy metabolism in mouse

Acrolein is a widespread contaminant found in both diet and environment, entering the human body through food, alcohol, smoking, and exposure to fuel combustion fumes. While prior studies have highlighted acrolein's harmful impact on oocyte quality and early embryonic development in vitro, the specific mechanisms by which acrolein affects the female reproductive system in vivo remain poorly understood. This study first confirmed that in vitro acrolein exposure disrupts spindle morphology and chromosome alignment during the mid-MI stage of oocyte development, thus hindering oocyte maturation. Besides, exposure to acrolein not only stunts growth in mice but also impairs ovarian development, decreases the ovarian coefficient, disrupts follicular development, and increases the count of atretic follicles in vivo. Additional research has shown that acrolein exposure reduces the activity of key enzymes in glycolysis, pyruvate metabolism, and the tricarboxylic acid cycle within the ovaries. It also suppresses mitochondrial complex expression and disturbs the balance between mitochondrial fission and fusion, as confirmed by metabolomic analyses. Moreover, acrolein exposure in vivo induced granulosa cell apoptosis and reduced oocyte number. In summary, acrolein exposure impairs glucose metabolism and induces mitochondrial dysfunction in the ovaries.

Chromosome-level genome assembly of a deep-sea Venus flytrap sea anemone sheds light upon adaptations to an extremely oligotrophic environment.

The Venus flytrap sea anemone Actinoscyphia liui inhabits the nutrient-limited deep ocean in the tropical western Pacific. Compared with most other sea anemones, it has undergone a distinct modification of body shape similar to that of the botanic flytrap. However, the molecular mechanism by which such a peculiar sea anemone adapts to a deep-sea oligotrophic environment is unknown. Here, we report the chromosomal-level genome of A. liui constructed from PacBio and Hi-C data. The assembled genome is 522 Mb in size and exhibits a continuous scaffold N50 of 58.4 Mb. Different from most other sea anemones, which typically possess 14-18 chromosomes per haplotype, A. liui has only 11. The reduced number of chromosomes is associated with chromosome fusion, which likely represents an adaptive strategy to economize energy in oligotrophic deep-sea environments. Comparative analysis with other deep-sea sea anemones revealed adaptive evolution in genes related to cellular autophagy (TMBIM6, SESN1, SCOCB and RPTOR) and mitochondrial energy metabolism (MDH1B and KAD2), which may aid in A. liui coping with severe food scarcity. Meanwhile, the genome has undergone at least two rounds of expansion in gene families associated with fast synaptic transmission, facilitating rapid responses to water currents and prey. Positive selection was detected on putative phosphorylation sites of muscle contraction-related proteins, possibly further improving feeding efficiency. Overall, the present study provides insights into the molecular adaptation to deep-sea oligotrophic environments and sheds light upon potential effects of a novel morphology on the evolution of Cnidaria.

MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart

Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.

MiR-125b-1-3p-mediated UQCRB inhibition facilitates mitochondrial metabolism disorders in a rat cellular senescencemodel

BackgroudCellular senescence is closely related to human aging and multiple aging-related diseases, and impaired mitochondrial energy metabolism is an important mechanism of cellular senescence. Notably, microRNA-125b-1-3p (miR-125b-1-3p) is a microRNA (miR, miRNA) that may be associated with mitochondrial energy metabolism. Ubiquinol-cytochrome c reductase binding protein (UQCRB) gene, predicted by bioinformatics tools to be targeted by miR-125b-1-3p, could serve as a novel diagnostic indicator and therapeutic target for cellular senescence-associated diseases, as well as a new idea for delaying aging. MethodsFirst, the dual-luciferase reporter gene assay was used to identify UQCRB as a target gene of miR-125b-1-3p. Next, miRNA interference technology was conducted to verify that miR-125b-1-3p could negatively regulate the expression of UQCRB. Subsequently, the influence of miR-125b-1-3p on mitochondrial energy metabolism function was explored by observing the internal substances and ultrastructure of mitochondria. Further, an in vitro model of cellular senescence was established in rat renal tubular epithelial cells, which was characterized by detecting senescence-related proteins p16 and p21 and beta-galactosidase (β-gal) activity. Finally, the mitochondrial energy metabolism function of hydrogen peroxide (H2O2)-incubated cells was explored. ResultsThe experimental results revealed that miR-125b-1-3p affected the mitochondrial energy metabolism function by inhibiting the target gene UQCRB. Meanwhile, the level of mitochondrial energy metabolism function in H2O2-incubated senescent cells was lower than that in normal cells. ConclusionIn this study, we identified the target gene, UQCRB, of miR-125b-1-3p, and demonstrated its role in the pathway of mitochondrial energy metabolism, as well as its possible effect on cellular senescence through this pathway. The ameliorative effects on cellular senescence can be further explored in subsequent studies to provide additional options for delaying aging or treating aging-related diseases.

Mechanisms of mitochondrial resilience in teleostean radial glia under hypoxic stress

Radial glial cells (RGCs) are remarkable cells, essential for normal development of the vertebrate central nervous system. In teleost fishes, RGCs play a pivotal role in neurogenesis and regeneration of injured neurons and glia. RGCs also exhibit resilience to environmental stressors like hypoxia via metabolic adaptations. In this study, we assessed the physiology of RGCs following varying degrees of hypoxia, with an emphasis on reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitophagy, and energy metabolism. Our findings demonstrated that hypoxia significantly elevated ROS production and induced MMP depolarization in RGCs. The mitochondrial disturbances were closely associated with increased mitophagy, based on the co-localization of mitochondria and lysosomes. Key mitophagy-related genes were also up-regulated, including those of the BNIP3/NIX mediated pathway as well as the FUNDC1 mediated pathway. Such responses suggest robust cellular mechanisms are initiated to counteract mitochondrial damage due to increasing hypoxia. A significant metabolic shift from oxidative phosphorylation to glycolysis was also observed in RGCs, which may underlie an adaptive response to sustain cellular function and viability following a reduction in oxygen availability. Furthermore, hypoxia inhibited the synthesis of mitochondrial complexes subunits in RGCs, potentially related to elevated HIF-2α expression with 3 % O2. Taken together, RGCs appear to exhibit complex adaptive responses to hypoxic stress, characterized by metabolic reprogramming and the activation of mitophagy pathways to mitigate mitochondrial dysfunction.

Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome.

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.

DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma.

Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial-mesenchymal transition (EMT). RNA-seq analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid-liquid phase separation (LLPS) to accumulate in the nucleus where it enhanced cytochrome-c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In OSCC patient samples, expression of DAZAP1 positively correlated with COX16, and high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis.

Physiological and transcriptomic changes of zebrafish (Danio rerio) in response to Isopropylate Triphenyl Phosphate (IPPP) exposure

Isopropylate Triphenyl Phosphate (IPPP), a novel organophosphorus flame retardant, has become a widespread environmental pollutant. However, the toxic effects and mechanisms of IPPP remain unclear. In this study, we evaluated the neurodevelopmental toxicity effects of IPPP on zebrafish embryonic development, neurobehavior, and physiological and transcriptomic changes. The results showed that IPPP induced adverse developments such as low survival rates and hatching rates, decreased body length and eye distance, and also led to increased heart rates and embryonic malformation rates. The developmental defects mainly included typical pericardial edema, eye deformities, and a reduction in the number of newborn neurons. Mitochondrial energy metabolism disorders and apoptosis of cardiomyocytes may be responsible for heart malformation. Behavioral results showed that IPPP caused abnormal changes in swimming speed, total swimming distance and trajectory, and showed a low-dose effect. In addition, the decreased activity of neurotransmitters such as acetylcholinesterase (AchE) and dopamine (DA), and the changes in genes related to the central nervous system (CNS) and metabolism pathway may be the causes of neurodevelopmental toxicity of IPPP. Meanwhile, IPPP induced oxidative stress and apoptosis, and changed the ATPase activity of zebrafish larvae by altering nuclear factor erythroid2-related factor 2 (Nrf2) and mitochondrial signaling pathways, respectively. Transcriptome sequencing results indicated that Cytochrome P450 and drug metabolism, Energy metabolism-related pathways, Glutathione metabolism, Retinoid acid (RA) and REDOX signaling pathways were significantly enriched, and most of the genes in these pathways were up-regulated after IPPP treatment, which may be new targets for IPPP-induced neurodevelopment. In summary, the results of this study provide an important reference for a comprehensive assessment of the toxic effects and health risks of the new pollutant IPPP.

Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer.

Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.

PTEN in kidney diseases: a potential therapeutic target in preventing AKI-to-CKD transition.

Renal fibrosis, a critical factor in the development of chronic kidney disease (CKD), is predominantly initiated by acute kidney injury (AKI) and subsequent maladaptive repair resulting from pharmacological or pathological stimuli. Phosphatase and tensin homolog (PTEN), also known as phosphatase and tensin-associated phosphatase, plays a pivotal role in regulating the physiological behavior of renal tubular epithelial cells, glomeruli, and renal interstitial cells, thereby preserving the homeostasis of renal structure and function. It significantly impacts cell proliferation, apoptosis, fibrosis, and mitochondrial energy metabolism during AKI-to-CKD transition. Despite gradual elucidation of PTEN's involvement in various kidney injuries, its specific role in AKI and maladaptive repair after injury remains unclear. This review endeavors to delineate the multifaceted role of PTEN in renal pathology during AKI and CKD progression along with its underlying mechanisms, emphasizing its influence on oxidative stress, autophagy, non-coding RNA-mediated recruitment and activation of immune cells as well as renal fibrosis. Furthermore, we summarize prospective therapeutic targeting strategies for AKI and CKD-treatment related diseases through modulation of PTEN.

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress

Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, invivo and invitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Metabolic regulating enhanced immunological activating nanocomposites for tumor microenvironment normalization and immunotherapy

The mitochondrial energy metabolic reprogramming of tumors leads to the hypoxic, acidic, and immunosuppressive microenvironment. To regulate the reprogrammed mitochondrial energy metabolism and the abnormal tumor microenvironment (TME) intracellularly and extracellularly, herein, we purposely constructed the metabolic regulating and immunological activating nanocomposites (NCs) formed by the manganese dioxide (MnO2) nanoparticles loaded with lactate oxidase (LOX), dichloroacetic acid (DCA) and SR-717, camouflaged by the cell membrane of tumors. After the NCs targeting to the tumors, the loaded DCA inhibited the glycolysis and triggered the produced pyruvate into mitochondria for further degradation. DCA also reduced the amount of CD39 and CD73, thereby promoting the accumulation of ATP intracellularly. The cascade of MnO2 and LOX catalyzed the lactate to pyruvate together with oxygen for the relief of the hypoxic and immunosuppressive TME. The regulation of the mitochondrial metabolism together with the degradation of lactate contributed to activating the immune cells. Meanwhile, the loaded SR-717 together with the release of Mn2+ activated the cyclic guanosine monophosphate adenosine monophosphate synthase/interferon gene stimulator signaling pathway for efficient antitumor effects and immunotherapy. Taken together, the designed multifunctional nanocomposites realized an effective tumor immunotherapy by regulating the reprogrammed mitochondrial energy metabolism intracellularly, relieving the abnormal TME and activating the innate antitumor immunological effects extracellularly. Our work established an approach to the enhanced immunotherapy by regulating the reprogrammed metabolism for efficient cancer treatment.