Physics of cellular energy metabolism

BackgroundChronically inflamed tissues as well as injured tissues are characterized by local hypoxia and – as a consequence – enhanced angiogenesis. The two transcription factors Hypoxia inducible factor (HIF)-1 and...

Hydrogen sulfide (H2S) has been increasingly recognized as a crucial inflammatory mediator in immune cells, particularly macrophages, due to its direct and indirect effects on cellular signaling, redox homeostasis, and energy metabolism. The intricate regulation of endogenous H2S production and metabolism involves the coordination of transsulfuration pathway (TSP) enzymes and sulfide oxidizing enzymes, with TSP’s role at the intersection of the methionine pathway and glutathione synthesis reactions. Additionally, H2S oxidation mediated by sulfide quinone oxidoreductase (SQR) in mammalian cells may partially control cellular concentrations of this gasotransmitter to induce signaling. H2S is hypothesized to signal through the posttranslational modification known as persulfidation, with recent research highlighting the significance of reactive polysulfides, a derivative of sulfide metabolism. Overall, sulfides have been identified as having promising therapeutic potential to alleviate proinflammatory macrophage phenotypes, which are linked to the exacerbation of disease outcomes in various inflammatory conditions. H2S is now acknowledged to have a significant influence on cellular energy metabolism by affecting the redox environment, gene expression, and transcription factor activity, resulting in changes to both mitochondrial and cytosolic energy metabolism processes. This review covers recent discoveries pertaining to the involvement of H2S in macrophage cellular energy metabolism and redox regulation, and the potential implications for the inflammatory response of these cells in the broader framework of inflammatory diseases.

Simple SummaryLysosomes are a critical component of the inner membrane system and are involved in various cellular biological processes, including macromolecular degradation, antigen presentation, intracellular pathogen destruction, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. Lysosomes are a critical regulator of cellular metabolism, cancer, metastasis, and resistance to anticancer therapy. Additionally, lysosomal activities play a crucial role in acute myeloid leukemia (AML) development and progression, as well as maintaining the hematopoietic stem cells (HSCs) pool. It has been shown that AML cells undergo metabolic alterations due to chemotherapy or targeted treatment. Thus, depending on the molecular subtypes of AML or the treatments involved, lysosomes could have a therapeutic potential.Lysosomes are cellular organelles that regulate essential biological processes such as cellular homeostasis, development, and aging. They are primarily connected to the degradation/recycling of cellular macromolecules and participate in cellular trafficking, nutritional signaling, energy metabolism, and immune regulation. Therefore, lysosomes connect cellular metabolism and signaling pathways. Lysosome’s involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer. Recent research advancements have demonstrated that lysosomes also regulate the maintenance and hemostasis of hematopoietic stem cells (HSCs), which play a critical role in the progression of acute myeloid leukemia (AML) and other types of cancer. Lysosomes regulate both HSCs’ metabolic networks and identity transition. AML is a lethal type of blood cancer with a poor prognosis that is particularly associated with aging. Although the genetic landscape of AML has been extensively described, only a few targeted therapies have been produced, warranting the need for further research. This review summarizes the functions and importance of targeting lysosomes in AML, while highlighting the significance of lysosomes in HSCs maintenance.

The effective condition monitoring of planetary gearboxes is important for making informed maintenance decisions and minimizing machine downtime. Traditional physics-based and data-driven approaches for condition monitoring of planetary gearboxes have inherent shortcomings that limit their practical application for remaining useful life prediction. Hybrid approaches show unique potential for performing diagnostics and prognostics of planetary gearboxes in situations where failure data is not available. Hybrid methods incorporate both physics-based and data-driven models that exploit their respective advantages. This work starts with a brief overview of the various challenges associated with vibration-based condition monitoring of planetary gearboxes and the characteristics of planetary gearboxes that complicate the condition monitoring process. Thereafter, the potential of hybrid methods to address these challenges is discussed. The respective advantages and disadvantages of physics-based and data-driven approaches are summarized and a short review of the use of hybrid methods in condition monitoring is presented. Finally, various considerations for developing hybrid methods for planetary gearbox diagnostics and prognostics are discussed. This includes considerations for selecting an appropriate hybrid framework, pre-processing of the measured vibration signal, physics-based modelling of a planetary gearbox, model calibration, health state estimation, and health state prediction.

Total parenteral nutrition (TPN) is a life-saving therapy for patients with intestinal failure, but it carries the risk of complications, including an increase in liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) after long-term use. Patients receiving chronic TPN are also exposed to metabolic stress from both the underlying disease and parenteral nutrition. The aim of this study was to compare the concentration of liver transaminases AST and ALT in relation to the rate of oxygen consumption in platelet mitochondria in patients receiving long-term TPN with the degree of oxidative stress induced by lipid emulsions, and to explain their role in cellular energy metabolism and changes in the liver based on the percentage of genomic DNA damage. The study group consisted of 86 TPN patients, while the control group consisted of 86 healthy volunteers who were fed only orally. The results of the study showed that the percentage of molecular oxygen depended on the type of lipid emulsion supplied. Analyzing time on TPN as a factor, we observed a decrease in percentage genomic DNA damage and an increase in percentage molecular oxygen in cells. It remains unclear whether TPN has a direct effect on genomic DNA damage and the level of molecular oxygen in cells during the course of treatment. In conclusion, this study provides important insights into the potential effects of TPN on liver enzymes and cellular metabolism. Further research is needed to better understand the underlying mechanisms and to develop strategies to minimize the risk of complications associated with TPN.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colonic mucosa. This condition can significantly affect the quality of life of those affected. While UC is common, its underlying mechanisms are not yet fully understood, highlighting the need for a comprehensive proteomic analysis of intestinal tissues to identify potential biological changes associated with the disease. This study aimed to investigate the proteomic differences in the intestinal tissues of patients with UC and healthy individuals using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics methods. The study employed a comprehensive proteomic analysis using LC-MS/MS to identify protein expression differences in intestinal tissues from five patients with UC versus five healthy controls. Subsequent bioinformatics analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, elucidated altered biological processes. We identified 194 upregulated and 323 downregulated proteins in the tissues of patients with UC, indicating a significant difference in protein expression. GO analysis revealed that the upregulated proteins were mainly involved in immune responses and metabolic processes, while the downregulated proteins were associated with organic and cellular metabolism. Additionally, KEGG pathway analysis showed that upregulated proteins were enriched in pathways related to ribosomes and phagosomes, whereas downregulated proteins were primarily linked to oxidative phosphorylation, thermogenesis, and the citric acid cycle, pointing to substantial changes in cellular energy metabolism. Protein-protein interaction (PPI) network analysis identified several key nodes, particularly those connected to ribosomal and phagocytic functions, which may play significant roles in the pathophysiology of UC. This study offers new insights into the biological mechanisms underlying UC and lays the foundation for future therapeutic strategies targeting these proteomic changes. Further experimental validation and clinical investigations are necessary to uncover additional mechanisms of UC and to facilitate the development of effective treatments.

Almost all cellular functions are powered by a continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors estrogen-related receptor α (ERRα) and ERRγ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERRα and ERRγ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERRα and ERRγ influence major cardiomyocyte energy consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis, and conduction genes. Mice lacking both ERRα and cardiac ERRγ develop severe bradycardia, lethal cardiomyopathy, and heart failure featuring metabolic, contractile, and conduction dysfunctions. These results illustrate that the ERR transcriptional pathway is essential to couple cellular energy metabolism with energy consumption processes in order to maintain normal cardiac function.

While much is known about the effects of the chemical microenvironment on cellular metabolism, mechanical cues have emerged as critical stimuli of intracellular metabolic pathways. Mechanical signals from the extracellular matrix (ECM), neighboring cells, and the microenvironment intersect with key regulators of cellular metabolism, often leading to changes in fundamental cell behaviors, including cell proliferation and migration. Here, we review recent work that has uncovered a role for mechanical cues from microenvironmental factors on cellular metabolism. We discuss how cell-ECM interactions and forces such as shear, tension, and compression affect cellular metabolic requirements and energy production. Importantly, mechanometabolism shapes both physiological homeostasis and pathological states, and further investigation has implications for understanding tissue function and disease progression and uncovering potential therapeutic strategies.

It is of great importance to define the manner in which cells are damaged and how intracellular derangement becomes irreversible during shock. When supply of both oxygen and substrates to cells is limited during shock, cellular energy metabolism of vital organs is severely depressed. In this experiment, the relationship was clarified between the reversibility of shock and the cellular energy status, from the viewpoint of hepatic energy change, mitochondrial redox state, ATP synthesis of isolated mitochondria, and fragility of mitochondrial membrane in rat livers. The derangement of energy metabolism passed through a series of four stages during hemorrhagic shock. At Stage I (initial stage), the cellular energy level decreased greatly due to marked energy consumption, without any organic damages in the mitochondria. Stage II (cell distress stage) showed that cellular energy imbalance occurred due to the depressed mitochondrial activity in vivo, although it was reversible when the blood supply was restored. Stage III (transitional stage) was the phase at which mitochondrial fragility increased severely. At Stage IV (terminal stage), mitochondria were markedly damaged organically and cellular energy metabolism was not remedied by any intensive therapies, which inevitably meant the death of vital organs.

Cellular energy production processes are composed of many Mg2+ dependent enzymatic reactions. In fact, dysregulation of Mg2+ homeostasis is involved in various cellular malfunctions and diseases. Recently, mitochondria, energy-producing organelles, have been known as major intracellular Mg2+ stores. Several biological stimuli alter mitochondrial Mg2+ concentration by intracellular redistribution. However, in living cells, whether mitochondrial Mg2+ alteration affect cellular energy metabolism remains unclear. Mg2+ transporter of mitochondrial inner membrane MRS2 is an essential component of mitochondrial Mg2+ uptake system. Here, we comprehensively analyzed intracellular Mg2+ levels and energy metabolism in Mrs2 knockdown (KD) cells using fluorescence imaging and metabolome analysis. Dysregulation of mitochondrial Mg2+ homeostasis disrupted ATP production via shift of mitochondrial energy metabolism and morphology. Moreover, Mrs2 KD sensitized cellular tolerance against cellular stress. These results indicate regulation of mitochondrial Mg2+ via MRS2 critically decides cellular energy status and cell vulnerability via regulation of mitochondrial Mg2+ level in response to physiological stimuli.

Molecular drivers of cellular metabolic reprogramming in melanoma

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.

The PPARGC1A gene plays a fundamental role in regulating cellular energy metabolism, including adaptive thermogenesis, mitochondrial biogenesis, adipogenesis, gluconeogenesis, and glucose/fatty acid metabolism. In a previous study, our group investigated seven SNPs in Mediterranean buffalo associated with milk production traits, and the current study builds on this research by exploring the regulatory influences of the PPARGC1A gene in buffalo mammary epithelial cells (BuMECs). Our findings revealed that knockdown of PPARGC1A gene expression significantly affected the growth of BuMECs, including proliferation, cell cycle, and apoptosis. Additionally, we observed downregulated triglyceride secretion after PPARGC1A knockdown. Furthermore, the critical genes related to milk production, including the STATS, BAD, P53, SREBF1, and XDH genes were upregulated after RNAi, while the FABP3 gene, was downregulated. Moreover, Silencing the PPARGC1A gene led to a significant downregulation of β-casein synthesis in BuMECs. Our study provides evidence of the importance of the PPARGC1A gene in regulating cell growth, lipid, and protein metabolism in the buffalo mammary gland. In light of our previous research, the current study underscores the potential of this gene for improving milk production efficiency and overall dairy productivity in buffalo populations.

IntroductionTrauma is a leading cause of death and despite trauma care improvements, survival rates remain unchanged for critically injured patients. Cellular energy stress occurs early following trauma, potentially representing a...

RNA-binding proteins (RBPs) are key players in coordinated post-transcriptional regulation of functionally related genes, defined as RNA regulons. RNA regulons play particularly critical roles in parasitic trypanosomes, which exhibit unregulated co-transcription of long unrelated gene arrays. In this report, we present a systematic analysis of an essential RBP, RBP42, in the mammalian-infective bloodstream form of African trypanosome and show that RBP42 is a key regulator of parasite's central carbon and energy metabolism. Using individual-nucleotide resolution UV cross-linking and immunoprecipitation to identify genome-wide RBP42-RNA interactions, we show that RBP42 preferentially binds within the coding region of mRNAs encoding core metabolic enzymes. Global quantitative transcriptomic and proteomic analyses reveal that loss of RBP42 reduces the abundance of target mRNA-encoded proteins, but not target mRNA, suggesting a positive translational regulatory role of RBP42. Significant changes in central carbon metabolic intermediates, following loss of RBP42, further support its critical role in cellular energy metabolism. Trypanosoma brucei infection, transmitted through the bite of blood-feeding tsetse flies, causes deadly diseases in humans and livestock. This disease, if left untreated, is almost always fatal. Existing therapies are toxic and difficult to administer. During T. brucei's lifecycle in two different host environments, the parasite progresses through distinctive life stages with major morphological and metabolic changes, requiring precise alteration of parasite gene expression program. In the absence of regulated transcription, post-transcriptional processes mediated by RNA-binding proteins play critical roles in T. brucei gene regulation. In this study, we show that the RNA-binding protein RBP42 plays crucial roles in cellular energy metabolic regulation of this important human pathogen. Metabolic dysregulation observed in RBP42 knockdown cells offers a breadth of potential interest to researchers studying parasite biology and can also impact research in general eukaryotic biology.