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Glycolysis is one of the primordial pathways of metabolism, playing a pivotal role in energy metabolism and biosynthesis. Glycolytic enzymes are known to form transient multi-enzyme assemblies. Here we examine the wider protein-protein interactions of plant glycolytic enzymes and reveal a moonlighting role for specific glycolytic enzymes in mediating the co-localization of mitochondria and chloroplasts. Knockout mutation of phosphoglycerate mutase or enolase resulted in a significantly reduced association of the two organelles. We provide evidence that phosphoglycerate mutase and enolase form a substrate-channelling metabolon which is part of a larger complex of proteins including pyruvate kinase. These results alongside a range of genetic complementation experiments are discussed in the context of our current understanding of chloroplast-mitochondrial interactions within photosynthetic eukaryotes. Protein-protein interactions are thought to channel substrates between consecutive enzymes during glycolysis. Here the authors show that Arabidopsis phosphoglycerate mutase and enolase can form a substrate-channelling metabolon and also play a moonlighting role in promoting colocalization of chloroplasts and mitochondria.

Deep understanding of sugar metabolite-protein interactions should provide implications on sugar metabolic reprogramming in human physiopathology. Although tremendous efforts have been made for determining individual event, global profiling of such interactome remains challenging. Here we describe thermal proteome profiling of glycolytic metabolite fructose-1,6-bisphosphate (FBP)-interacting proteins. Our results reveal a chemical signaling role of FBP which acts as a phosphate donor to activate phosphoglycerate mutase 1 (PGAM1) and contribute an intrapathway feedback for glycolysis and cell proliferation. At molecular level, FBP donates either C1 -O -phosphate or C6 -O -phosphate to the catalytic histidine of PGAM1 to form 3-phosphate histidine (3-pHis) modification. Importantly, structure-activity relationship studies facilitate the discovery of PGAM1 orthostatic inhibitors which can potentially restrain cancer cell proliferation. Collectively we have profiled a spectrum of FBP interactome, and discovered a unique covalent signaling function of FBP that supports Warburg effect via histidine phosphorylation which inspires the development of pharmacological tools targeting sugar metabolism. Sugar metabolic reprogramming is a hallmark of various diseases including cancer. Here, the authors report a thermal proteome profiling (TPP)-based strategy to profile the FBP interactome and describe a chemical signaling role for FBP, contributing to an intrapathway feedback for glycolysis and cell proliferation.

Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced, it may lead to poor reproductive cell quality and aging. However, Phosphoglycerate translocase 5 (PGAM5), located in the mitochondrial membrane, is associated with necroptosis, apoptosis, and mitophagy, although the underlying mechanisms associated with ovarian aging remain unknown. Therefore, we attempted to uncover whether the high phosphoglycerate mutant enzyme family member 5 (PGAM5) expression is associated with female infertility in cumulus cells, and aims to find out the underlying mechanism of action of PGAM5. We found that PGAM5 is highly expressed and positively associated with aging, and has the potential to help maintain and regulate mitochondrial dynamics and metabolic reprogramming in aging granulosa cells, ovaries of aged female mice, and elderly patients. PGAM5 undergoes activation in the aging group and translocated to the outer membrane of mitochondria, co‐regulating DRP1; thereby increasing mitochondrial fission. A significant reduction in the quality of mitochondria in the aging group, a serious imbalance, and a significant reduction in energy, causing metabolism shift toward glycolysis, were also reported. Since PGAM5 is eliminated, the mitochondrial function and metabolism of aging cells are partially reversed. A total of 70 patients undergoing in vitro fertilization (IVF) treatment were recruited in this clinical study. The high expression of PGAM5 in the cumulus cells is negatively correlated with the pregnancy rate of infertile patients. Hence, PGAM5 has immense potential to be used as a diagnostic marker. Li et al. found that Phosphoglycerate mutase family member 5 (PGAM5) levels are increased during female reproductive system aging and are accompanied by mitochondrial division. Overexpression of PGAM5 diminished age‐related fertility, providing evidence for a pathogenic effect of increased PGAM5. This study reveals a previously unrecognized molecular mechanism of age‐related infertility.

The primordial cyanobacteria were responsible for developing oxygenic photosynthesis early in evolution. In the pathways of fixed carbon allocation, the co-factor-independent phosphoglycerate mutase (iPGAM) plays a crucial role by directing the first CO 2 fixation product, 3-phosphoglycerate, toward central anabolic glycolytic-derived pathways. This work reveals a distinct evolution of iPGAM within oxygenic photosynthetic organisms. We have identified two specific segments in cyanobacterial iPGAMs that affect the control of iPGAM activity through its specific interactor protein PirC. This understanding of iPGAM has allowed us to engineer cyanobacterial strains with altered carbon fluxes. Since cyanobacteria can directly convert CO 2 into valuable products, our results demonstrate a novel approach for developing a chassis for biotechnical use.

Phosphoglycerate mutase 1 (PGAM1) is a recently identified key catalytic enzyme in aerobic glycolysis. Recent literature has documented that dysregulated PGAM1 expression is associated with tumorigenesis in various cancers. However, the expression status and biological function of PGAM1 in non-small-cell lung cancer (NSCLC) are poorly elucidated. In this study, we found that PGAM1 was overexpressed in NSCLC tissues and that high expression of PGAM1 was associated with poor prognosis in NSCLC patients. Functionally, gain- and loss-of-function analysis showed that PGAM1 promoted proliferation and invasion in vitro, and facilitated tumor growth in vivo. Mechanistically, the transforming growth factor-β (TGF-β) signaling pathway was also markedly impaired in response to PGAM1 silencing. Additionally, we verified that PGAM1 was inhibited by miR-3614-5p via direct targeting of its 3’-untranslated regions in a hypoxia-independent manner. Furthermore, overexpression of miR-3614-5p attenuated NSCLC cell proliferation and invasion, and these effects could be partially reversed by reintroduction of PGAM1. Conclusively, our results suggest that the miR-3614-5p/PGAM1 axis plays a critical role during the progression of NSCLC, and these findings may provide a potential target for the development of therapeutic strategies for NSCLC patients.

Osteoarthritis (OA) is the most common degenerative joint disease; however, its etiopathogenesis is not completely understood. Here we show a role for NUDT7 in OA pathogenesis. Knockdown of NUDT7 in normal human chondrocytes results in the disruption of lipid homeostasis. Moreover, Nudt7 −/− mice display significant accumulation of lipids via peroxisomal dysfunction, upregulation of IL-1β expression, and stimulation of apoptotic death of chondrocytes. Our genome-wide analysis reveals that NUDT7 knockout affects the glycolytic pathway, and we identify Pgam1 as a significantly altered gene. Consistent with the results obtained on the suppression of NUDT7 , overexpression of PGAM1 in chondrocytes induces the accumulation of lipids, upregulation of IL-1β expression, and apoptotic cell death. Furthermore, these negative actions of PGAM1 in maintaining cartilage homeostasis are reversed by the co-introduction of NUDT7 . Our results suggest that NUDT7 could be a potential therapeutic target for controlling cartilage-degrading disorders. Osteoarthritis is a common joint disease that is a major public health problem. Here, the authors identify a role for the NUDT7 protein in pathogenesis of the disease, and report the potential for NUDT7 to be a target for future therapies.

Ovarian cancer represents one of the most prevalent gynecological malignancies with a poor prognosis. Targeting glycolytic pathways has emerged as a novel cancer therapeutic strategy. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification plays a regulatory role in cancer glycolysis. Phosphoglycerate mutase 1 (PGAM1) functions as a critical glycolytic enzyme and potential therapeutic target in oncology. This study investigated the functional role and underlying mechanisms of NAT10 in ovarian cancer progression. Cellular glycolysis was assessed through glucose uptake measurements, lactate production quantification, and extracellular acidification rate analysis. Cell stemness characteristics were evaluated using sphere formation assays and western blot analysis. Molecular mechanisms were explored via quantitative real-time PCR, RNA immunoprecipitation (RIP), ac4C-specific RIP, dot blot analysis, and dual-luciferase reporter assays. Elevated NAT10 expression and ac4C modification levels were observed in ovarian cancer cells. NAT10 silencing significantly inhibited both cell stemness properties and glycolytic activity. Mechanistically, NAT10 enhanced PGAM1 mRNA stability through ac4C modification. Re-expression of PGAM1 reversed the functional effects induced by NAT10 depletion in ovarian cancer cells. Furthermore, in vivo tumor growth experiments demonstrated that NAT10 promotes tumorigenesis. Our findings demonstrate that NAT10 facilitates ovarian cancer progression by mediating ac4C modification of PGAM1. This study identifies a novel and potentially effective therapeutic target for ovarian cancer treatment.

Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis. However, the precise role and other biological functions of PGAM1 remain unclear. Here, we report that PGAM1 expression is upregulated and related to poor prognosis in patients with breast cancer (BC). Functional experiments showed that knockdown of PGAM1 could suppress the proliferation, invasion, migration, and epithelial–mesenchymal transition of BC cells. Through RNA sequencing, we found that argininosuccinate synthase 1 (ASS1) expression was markedly upregulated in BC cells following PGAM1 knockdown, and it is required to suppress the malignant biological behavior of BC cells. Importantly, we demonstrated that PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB axis. In vivo experiments further validated that PGAM1 promoted tumor growth in BC by altering ASS1 expression. Finally, immunohistochemical analysis showed that downregulated ASS1 levels were associated with PGAM1 expression and poor prognosis in patients with BC. Our study provides new insight into the regulatory mechanism of PGAM1‐mediated BC progression that might shed new light on potential targets and combination therapeutic strategies for BC treatment. Knockdown of phosphoglycerate mutase 1 (PGAM1) could reconstruct the expression of ASS1 in breast cancer (BC) cells, resulting in a decrease in tumor growth and exerting antitumor effects via cAMP/AMPK/CEBPB axis. These findings constructed a new theoretical background for PGAM1‐mediated tumor progression, and the elements in this molecular network could be the target of BC treatment.

The ability of Staphylococcus aureus and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for manganese sensitizing S. aureus to host-imposed manganese starvation. The current investigations were undertaken to elucidate how S. aureus copes with the need to consume glucose when metal-limited by the host. A critical component of host defense is production of the manganese binding protein calprotectin. S. aureus has two variants of phosphoglycerate mutase, one of which is manganese-dependent, GpmI, and another that is manganese-independent, GpmA. Leveraging the ability to impose metal starvation in culture utilizing calprotectin revealed that the loss of GpmA, but not GpmI, sensitized S. aureus to manganese starvation. Metabolite feeding experiments revealed that the growth defect of GpmA when manganese-starved was due to a defect in glycolysis and not gluconeogenesis. Loss of GpmA reduces the ability of S. aureus to cause invasive disease in wild type mice. However, GpmA was dispensable in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of S. aureus to overcome manganese limitation during infection. Cumulatively, these observations suggest that expressing a metal-independent variant enables S. aureus to consume glucose while mitigating the negative impact that glycolysis has on the cellular demand for manganese. S. aureus is not the only bacterium that expresses manganese-dependent and -independent variants of phosphoglycerate mutase. Similar results were also observed in culture with Salmonella enterica serovar Typhimurium mutants lacking the metal-independent isozyme. These similar observations in both Gram-positive and Gram-negative pathogens suggest that expression of metal-independent glycolytic isozymes is a common strategy employed by bacteria to survive in metal-limited environments, such as the host.

Stomatal movements require massive changes in guard cell osmotic content, and both stomatal opening and stomatal closure have been shown to be energy-requiring processes. A possible role for glycolysis in contributing to the energetic, reducing requirements, or signalling processes regulating stomatal movements has not been investigated previously. Glycolysis, oxidization of glucose to pyruvate, is a central metabolic pathway and yields a net gain of 2 ATP and 2 NADH. 2,3-biphosphoglycerate-independent phosphoglycerate mutase (iPGAM) is a key enzymatic activity in glycolysis and catalyses the reversible interconversion of 3-phosphoglycerate to 2-phosphoglycerate. To investigate functions of iPGAMs and glycolysis in stomatal function and plant growth, Arabidopsis insertional mutants in At1g09780 and At3g08590, both of which have been annotated as iPGAMs on the basis of sequence homology, were identified and characterized. While single mutants were indistinguishable from the wild type in all plant phenotypes assayed, double mutants had no detectable iPGAM activity and showed defects in blue light-, abscisic acid-, and low CO 2 -regulated stomatal movements. Vegetative plant growth was severely impaired in the double mutants and pollen was not produced. The data demonstrate that iPGAMs and glycolytic activity are critical for guard cell function and fertility in Arabidopsis.