Metabolic Adaptation Research Articles

Hypoxia LUAD H1975 cell-derived exosomal miR-671-3p promotes angiogenesis via regulating KLF2-VEGFR2 axis

For solid tumors, hypoxia is associated with disease aggressiveness and poor outcomes. In addition to undergoing broad intracellular molecular and metabolic adaptations, hypoxic tumor cells extensively communicate with their microenvironments to facilitate conditions favorable for their survival, growth, and metastasis. This communication is mediated by diverse secretory factors, including exosomes (extracellular vesicles of endosomal origin). Exosomal cargo is altered considerably by hypoxia, with significant impacts on tumor-cell communication with both local and distant microenvironments. Exosomes released by cancer cells influence the tumor environment to accelerate metastasis. While tumor-derived exosomes have been identified as a major driver of premetastatic niche formation at distant sites, this mechanism in lung adenocarcinoma (LUAD) remains unclear. We found that miR-671-3p in exosomes derived from H1975 under hypoxic conditions target Krüppel-like factor 2 (KLF2) to regulate VEGFR2 expression in endothelial cells to promote angiogenesis. In addition, miR-671-3p is expressed at high levels in circulating exosomes isolated from patients with LUAD. Our study suggests that exosome miR-671-3p is involved in the formation of premetastatic niche and may serve as a blood-based biomarker for LUAD metastasis.

Combined Effects of Ketogenic Diet and Aerobic Exercise on Skeletal Muscle Fiber Remodeling and Metabolic Adaptation in Simulated Microgravity Mice

Objective: Prolonged microgravity environments impair skeletal muscle homeostasis by triggering fiber-type transitions and metabolic dysregulation. Although exercise and nutritional interventions may alleviate disuse atrophy, their synergistic effects under microgravity conditions remain poorly characterized. This study investigated the effects of an 8-week ketogenic diet combined with aerobic exercise in hindlimb-unloaded mice on muscle fiber remodeling and metabolic adaptation. Methods: Seven-week-old male C57BL/6J mice were randomly divided into six groups: normal diet control (NC), normal diet with hindlimb unloading (NH), normal diet with hindlimb unloading and exercise (NHE), ketogenic diet control (KC), ketogenic diet with hindlimb unloading (KH), and ketogenic diet with hindlimb unloading and exercise (KHE). During the last two weeks of intervention, hindlimb unloading was applied to simulate microgravity. Aerobic exercise groups performed moderate-intensity treadmill running (12 m/min, 60 min/day, and 6 days/week) for 8 weeks. Body weight, blood ketone, and glucose levels were measured weekly. Post-intervention assessments included the respiratory exchange ratio (RER), exhaustive exercise performance tests, and biochemical analyses of blood metabolic parameters. The skeletal muscle fiber-type composition was evaluated via immunofluorescence staining, lipid deposition was assessed using Oil Red O staining, glycogen content was analyzed by Periodic Acid–Schiff (PAS) staining, and gene expression was quantified using quantitative real-time PCR (RT-qPCR). Results: Hindlimb unloading significantly decreased body weight, induced muscle atrophy, and reduced exercise endurance in mice. However, the combination of KD and aerobic exercise significantly attenuated these adverse effects, as evidenced by increased proportions of oxidative muscle fibers (MyHC-I) and decreased proportions of glycolytic fibers (MyHC-IIb). Additionally, this combined intervention upregulated the expression of lipid metabolism-associated genes, including CPT-1b, HADH, PGC-1α, and FGF21, enhancing lipid metabolism and ketone utilization. These metabolic adaptations corresponded with improved exercise performance, demonstrated by the increased time to exhaustion in the KHE group compared to other hindlimb unloading groups. Conclusions: The combination of a ketogenic diet and aerobic exercise effectively ameliorates simulated microgravity-induced skeletal muscle atrophy and endurance impairment, primarily by promoting a fiber-type transition from MyHC-IIb to MyHC-I and enhancing lipid metabolism gene expression (CPT-1b, HADH, and PGC-1α). These findings underscore the potential therapeutic value of combined dietary and exercise interventions for mitigating muscle atrophy under simulated microgravity conditions.

Impact of Tetracycline Stress on Water Quality and Rhizosphere Microbial Communities of Eichhornia crassipes: Implications for Bioremediation

To examine the impact of antibiotic contamination on water quality and rhizospheric microbial communities, a simulated cultivation experiment was employed to investigate the potential impacts of tetracycline (Tet) stress on water quality and microbial community composition in the rhizosphere of Eichhornia crassipes (E. crassipes), with a focus on its implications for bioremediation strategies. The results showed a significant disruption in microbial diversity and community structure in the rhizosphere at varying accumulated Tet concentrations (0, 2, 5, and 10 mg·L−1). The microbial communities displayed resilience and functional stability from the low (2 mg·L−1) to moderate (5 mg·L−1) accumulated Tet concentrations; while significant root decay and a marked decline in microbial diversity were observed at the high (10 mg·L−1) accumulated Tet concentration. Some bacterial taxa, including Rhizobiaceae (0.34%), Comamonadaceae (0.37%), and Chitinophagaceae (0.38%), exhibited notable enrichment under Tet stress, underscoring their functional roles in nitrogen cycling, organic matter decomposition, and antibiotic degradation. Physicochemical changes in the rhizosphere, such as shifts in low-molecular-weight organic acids (LMWOAs), nutrient cycling, and total organic carbon (TOC), revealed Tet-induced metabolic adaptations and environmental alterations. Correlation analysis between environmental factors and dominant operational taxonomic units (OTUs) highlighted the putative intricate interplay between microbial activity and Tet stress. These findings underscore the dual impact of Tet as both a stressor and a selective agent, favoring antibiotic-resistant taxa while suppressing sensitive groups. This study provides foundational insights into the ecological and functional dynamics of microbial communities under antibiotic contamination conditions and highlights the potential of rhizospheric microbial communities in the rhizosphere for bioremediation in Tet-polluted ecosystems.

Inside the Belly of the Beast: Exploring the Gut Bacterial Diversity of Gonipterus sp. n. 2

The Eucalyptus snout beetle (Gonipterus sp. n. 2) is a destructive invasive pest of Eucalyptus plantations, responsible for significant defoliation and wood yield losses globally. Native to Australia, this beetle has adapted to thrive on diverse Eucalyptus hosts, overcoming their chemical defences. However, the mechanisms by which Gonipterus tolerates or utilises these plant defence metabolites remain poorly understood. In South Africa, Gonipterus sp. n. 2 poses a significant threat to Eucalyptus plantations by causing extensive defoliation and leading to substantial reductions in growth and wood production. This study investigates the relationship between diet, host Eucalyptus species, and the gut microbiome of Gonipterus sp. n. 2. Using controlled feeding experiments, beetles were reared on artificial, semi-artificial, and natural diets, as well as two Eucalyptus genotypes with distinct secondary metabolite profiles. High-throughput 16S rDNA sequencing and gas chromatography-mass spectrometry (GC–MS) revealed significant shifts in gut bacterial diversity and composition across diets. Natural diets supported the most diverse microbial communities, while artificial diets fostered a homogenised microbiome dominated by opportunistic taxa like Serratia. Host-specific effects were observed in frass microbiota, with substantial biotransformation of monoterpenes into less toxic derivatives. The results highlight the plasticity of Gonipterus gut microbiota, which enables metabolic adaptability and resilience in diverse environments. This microbial flexibility underpins the invasiveness of Gonipterus, emphasising the role of gut symbionts in overcoming host chemical defences. Understanding these interactions offers novel insights for microbiome-targeted pest management strategies, providing a sustainable approach to mitigate the impact of Gonipterus on global Eucalyptus forestry.

The microbiota-m6A-metabolism axis: Implications for therapeutic strategies in gastrointestinal cancers.

The microbiota-m6A-metabolism axis: Implications for therapeutic strategies in gastrointestinal cancers.

Lysosomes and LAMPs as Autophagy Drivers of Drug Resistance in Colorectal Cancer

Colorectal cancer (CRC) is among the most malignant pathologies worldwide. A major factor contributing to the poor prognosis of neoplastic diseases is the development of drug resistance. It significantly reduces the utility of most therapeutic protocols and necessitates the search for novel biomarkers and treatment strategies to combat cancer. An evolutionarily conserved catabolic mechanism, autophagy maintains nutrient recycling and metabolic adaptation and is also closely related to carcinogenesis, playing a dual role. Autophagy inhibition can limit the growth of tumors and improve the response to cancer therapeutics. Lysosomes, key players in autophagy, are also considered promising targets for anticancer treatment. There are still insufficient data on the role of poorly studied glycoproteins related to autophagy, such as the lysosome-associated membrane glycoproteins (LAMPs). They can act as multifunctional molecules involved in a multitude of processes like autophagy and cancer development. In the current review, we summarize the recent data on the double-faceted role of autophagy in cancer with a focus on drug resistance in CRC and on the roles of lysosomes and LAMPs in these interconnected processes. Several lysosomotropic drugs are discussed as options to overcome cancer cell chemoresistance. The complex networks that underline defined autophagic pathways in the context of CRC carcinogenesis and the role of autophagy, especially of LAMPs as drivers of drug resistance, are outlined.

Protein-enriched intermittent meal replacement combined with moderate-intensity training for weight loss and body composition in overweight women

The global rise in overweight and obesity has been exacerbated by sedentary lifestyles and suboptimal dietary habits. Traditional weight loss methods often struggle with adherence due to restrictive diets and metabolic adaptations. Intermittent meal replacement (IMR), incorporating formulated protein-enriched nutritional shakes, has emerged as a potential strategy for weight management. However, its combined effects with moderate-intensity continuous training (MICT) remain underexplored. This study aimed to evaluate the impact of a weight loss method incorporating formulated protein-enriched nutritional shake IMR in conjunction with MICT workout for overweight female adults. This 8-week parallel randomized controlled trial investigated the impact of protein-enriched IMR combined with MICT on weight loss and body composition in overweight female adults. Participants were randomly assigned to either the MICT group or MICT + IMR group. Body composition, hematological, and urinary biomarkers were assessed pre- and post-intervention. The MICT + IMR Group achieved a greater reduction in body weight (-3.70 kg vs. -1.17 kg, p < 0.001) and body fat mass (-2.25 kg vs. -1.19 kg, p < 0.001) compared to the MICT group. Additionally, fasting blood glucose and insulin levels significantly improved in the MICT + IMR Group, suggesting enhanced metabolic regulation. IMR, when combined with MICT, is a viable strategy for short-term weight loss in overweight women, offering improved fat reduction and metabolic benefits compared to exercise alone.Trial registration: Chinese Clinical Trail Registry, ChiCTR2300076750. Registered 17 October 2023, https://www.chictr.org.cn/bin/project/edit?pid=197611.

The vertical distribution and metabolic versatility of complete ammonia oxidizing communities in mangrove sediments.

The vertical distribution and metabolic versatility of complete ammonia oxidizing communities in mangrove sediments.

NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.

The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.

17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2-ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.

Membrane modification and adaptation of metabolism by Acinetobacter baumannii prompts resistance to antimicrobial activity of outer membrane perturbing peptide L8.

Multidrug resistant (MDR) Acinetobacter baumannii has emerged as one of the most concerning nosocomial pathogens worldwide. One approach to target MDR A. baumannii is treatment with synergistic combinations of outer membrane-permeabilizing antimicrobial peptides (AMP) and antibiotics that otherwise only act against Gram-positive bacteria. Resistance against AMPs is rarely observed, especially when administered in combination with other drugs. Recently, we described the synergistic antimicrobial activity of AMPs L8 and L8S1 with rifampicin against a clinical isolate of A. baumannii. In the current work we explore the mechanisms of action of these peptides. We demonstrate that L8 and L8S1 perturb the cell envelope of A. baumannii. Moreover, we show that resistance against peptide L8 could be acquired in vitro either by increasing the amount of PE lipid on the surface or by increasing biofilm formation. Interestingly, the resistance to the antimicrobial activity of the peptides did not affect membrane perturbation or synergistic activity of the peptides with rifampicin, suggesting a dual mechanism of action for these peptides.

Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.

Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.

Metagenomic analysis reveals microbial drivers of heat resistance in dairy cattle

Heat stress poses a significant challenge to dairy cattle, leading to adverse physiological effects, reduced milk yield, impaired reproduction performance and economic losses. This study investigates the role of the rumen microbiome in mediating heat resistance in dairy cows. Using the entropy-weighted TOPSIS method, we classified 120 dairy cows into heat-resistant (HR) and heat-sensitive (HS) groups based on physiological and biochemical markers, including rectal temperature (RT), respiratory rate (RR), salivation index (SI) and serum levels of potassium ion (K+), heat shock protein 70 (HSP70) and cortisol. Metagenomic sequencing of rumen fluid samples revealed distinct microbial compositions and functional profiles between the two groups. HR cows exhibited a more cohesive and functionally stable microbiome, dominated by taxa such as Ruminococcus flavefaciens and Succiniclasticum, which are key players in fiber degradation and short-chain fatty acid production. Functional analysis highlighted the enrichment of the pentose phosphate pathway (PPP) in HR cows, suggesting a metabolic adaptation that enhances oxidative stress management. In contrast, HS cows showed increased activity in the tricarboxylic acid (TCA) cycle, pyruvate metabolism and other energy-intensive pathways, indicating a higher metabolic burden under heat stress. These findings underscore the critical role of the rumen microbiome in modulating heat resistance and suggest potential microbiome-based strategies for improving dairy cattle resilience to climate change.

Targeting SHMT2‐mediated membrane phospholipid remodeling for enhanced anti‐GCSCs treatment

AbstractCancer stem cells exhibit flexible metabolic profiles. However, the underlying mechanisms for differential metabolic pathways affecting stemness maintenance in gastric cancer are poorly understood. Here, we reveal the role of serine hydroxymethyltransferase‐2 (SHMT2)/serine‐mediated crosstalk between one‐carbon metabolism and lipid metabolism in the stemness maintenance of gastric cancer. Clinically, SHMT2 was significantly highly expressed in Gastric cancer cells (GCs) and gastric cancer stem cells, and was associated with clinical malignant features and poor prognosis in gastric cancer patients. Mechanistically, inhibition of SHMT2 expression resulted in diminished serine levels in one‐carbon metabolism, which subsequently modified the composition and fluidity of membrane phospholipids, leading to a reduction in lipid rafts within cellular membranes. The remodeling of membrane phospholipids hindered the localization of γ‐secretase to lipid rafts, thereby inhibiting the cleavage of CD44 and the subsequent production of CD44‐ICD. Consequently, the transcriptional regulation of c‐Myc and KLF4 by CD44‐ICD was reduced, ultimately disrupting the maintenance of stemness in gastric cancer cells. Together, these results provide compelling evidence for the metabolic adaptability of cancer stem cells, and the SHMT2/serine/lipid rafts signaling axis holds promise as a potential biomarker for the diagnosis and prognosis of gastric cancer. Furthermore, we synthesized HA‐Exo‐si SHMT2 to investigate targeted therapy for GC, offering a novel approach for the clinical treatment of gastric cancer.

Neurological Manifestations Associated with Exercise at Altitude.

The effects that exercise at altitude has on the neurological system are diverse and still not well studied, and range from metabolic adaptations to modification of cerebral blood flow and neurotransmitters. In this review we summarise changes with exercise intensity, the implications of ascent, cognitive impairment, psychosis-like symptoms, the role of exercise in the development and prevention of AMS, and use of free radical scavengers to enhance sports performance and acclimatization. We discuss the impact of oxidative stress in hypobaric hypoxia and reactive oxygen species (ROS) production and its consequences, with special focus on exercise at altitude. Finally we consider how moderate intensity exercise could help prevent AMS, and the necessity of research on high intensity exercise with elevated rate of ascent, the development of specific tools of cognitive assessment, and the role of free-radical scavengers in the prevention of AMS and neurological symptoms.

Comparative analyses of the gut microbiome of two sympatric rodent species, Myodes rufocanus and Apodemus peninsulae, in northeast China based on metagenome sequencing.

The gut microbiota is integral to an animal's physiology, influencing nutritional metabolism, immune function, and environmental adaptation. Despite the significance of gut microbiota in wild rodents, the Korean field mouse (Apodemus peninsulae) and the gray red-backed vole (Myodes rufocanus) remain understudied. To address this, a metagenomic sequencing analysis of the gut microbiome of these sympatric rodents in northeast China's temperate forests was conducted. Intestinal contents were collected from A. peninsulae and M. rufocanus within the Mudanfeng National Nature Reserve. High-throughput sequencing elucidated the gut microbiome's composition, diversity, and functional pathways. Firmicutes, Bacteroidetes, and Proteobacteria were identified as the dominant phyla, with M. rufocanus showing greater microbiome diversity. Key findings indicated distinct gut bacterial communities between the species, with M. rufocanus having a higher abundance of Proteobacteria. The gut microbiota of A. peninsulae and M. rufocanus differed marginally in functional profiles, specifically in the breakdown of complex carbohydrates, which might reflect their distinct food preferences albeit both being herbivores with a substantial dietary overlap. The investigation further elucidated gut microbiota's contributions to energy metabolism and environmental adaptation mechanisms. This study aligns with information on rodent gut microbiota in literature and highlights the two understudied rodent species, providing comparative data for future studies investigating the role of gut microbiota in wildlife health and ecosystem functioning.

Spatial ecology of the Neisseriaceae family in the human oral cavity.

The human oral microbiome is a diverse ecosystem in which bacterial species have evolved to occupy specific niches within the oral cavity. The Neisseriaceae family, which includes human oral species in the genera Neisseria, Eikenella, Kingella, and Simonsiella, plays a significant role in both commensal and pathogenic relationships. In this study, we investigate the distribution and functional adaptations of Neisseriaceae species across oral habitats, focusing on their site tropisms and ecological roles. We employed a metapangenomic approach in which a curated set of reference genomes representing Neisseriaceae diversity was used for competitive mapping of metagenomic reads. Our analysis revealed distinct habitat preferences among Neisseriaceae species, with Kingella oralis, Neisseria elongata, and Neisseria mucosa primarily found in dental plaque; Neisseria subflava on the tongue dorsum; and Neisseria cinerea in the keratinized gingiva. Functional enrichment analyses identified genes and pathways underpinning habitat-specific adaptations. Plaque specialists showed metabolic versatility, with adaptations in nitrogen metabolism, including nitrate reduction and denitrification, lysine degradation, and galactose metabolism. Tongue dorsum specialists exhibited adaptations including enhanced capabilities for amino acid biosynthesis, short-chain fatty acid and glycerol transport, as well as lipopolysaccharide glycosylation, which may aid in resisting antimicrobial peptides and maintaining membrane integrity. These findings provide insights into the ecological roles and adaptive strategies of Neisseriaceae species within the human oral microbiome and establish a foundation for exploring functional specialization and microbial interactions in these niches.IMPORTANCEUnraveling the distribution and functional adaptations of Neisseriaceae within the human oral microbiome is essential for understanding the roles of these abundant and prevalent commensals in both health and disease. Through a metapangenomic approach, we uncovered distinct habitat preferences of various Neisseriaceae taxa across the oral cavity and identified key genetic traits that may drive their habitat specialization and role in host-microbe interactions. These insights enhance our understanding of the microbial dynamics that shape oral microbial ecology, offering potential pathways for advancing oral health research.

Alternative splicing of uromodulin enhances mitochondrial metabolism for adaptation to stress in kidney epithelial cells.

In the kidney, cells of thick ascending limb of the loop of Henle (TAL) are resistant to ischemic injury, despite high energy demands. This adaptive metabolic response is not fully understood even though the integrity of TAL cells is essential for recovery from acute kidney injury (AKI). TAL cells uniquely express uromodulin, the most abundant protein secreted in healthy urine. Here, we demonstrate that alternative splicing generates a conserved intracellular isoform of uromodulin, which contributes to metabolic adaptation of TAL cells. This splice variant was induced by oxidative stress and was up-regulated by AKI that is associated with recovery, but not by severe AKI and chronic kidney disease (CKD). This intracellular variant was targeted to the mitochondria, increased NAD+ and ATP levels, and protected TAL cells from hypoxic injury. Augmentation of this variant using antisense oligonucleotides after severe AKI improved the course of injury. These findings underscore an important role of condition-specific alternative splicing in adaptive energy metabolism to hypoxic stress. Enhancing this protective splice variant in TAL cells could become a novel therapeutic intervention for AKI.

Enzyme-constrained metabolic model of Treponema pallidum identified glycerol-3-phosphate dehydrogenase as an alternate electron sink

ABSTRACT Treponema pallidum , the causative agent of syphilis, poses a significant global health threat. Its strict reliance on host-derived nutrients and difficulties in in vitro cultivation have impeded detailed metabolic characterization. In this study, we present iTP251, the first genome-scale metabolic model of T. pallidum , reconstructed and extensively curated to capture its unique metabolic features. These refinements included the curation of key reactions such as pyrophosphate-dependent phosphorylation and pathways for nucleotide synthesis, amino acid synthesis, and cofactor metabolism. The model demonstrated high predictive accuracy, validated by a MEMOTE score of 92%. To further enhance its predictive capabilities, we developed ec-iTP251, an enzyme-constrained version of iTP251, incorporating enzyme turnover rate and molecular weight information for all reactions having gene-protein-reaction associations. Ec-iTP251 provides detailed insights into protein allocation across carbon sources, showing strong agreement with proteomics data (Pearson’s correlation of 0.88) in the central carbon pathway. Moreover, the thermodynamic analysis revealed that lactate uptake serves as an additional ATP-generating strategy to utilize unused proteomes, albeit at the cost of reducing the driving force of the central carbon pathway by 27%. Subsequent analysis identified glycerol-3-phosphate dehydrogenase as an alternative electron sink, compensating for the absence of a conventional electron transport chain while maintaining cellular redox balance. These findings highlight T. pallidum ’s metabolic adaptations for survival and redox balance in nutrient-limited, extracellular host environments, providing a foundation for future research into its unique bioenergetics. IMPORTANCE This study advances our understanding of Treponema pallidum , the syphilis-causing pathogen, through the reconstruction of iTP251, the first genome-scale metabolic model for this organism, and its enzyme-constrained version, ec-iTP251. The work addresses the challenges of studying T. pallidum , an extracellular, host-adapted pathogen, due to its strict dependence on host-derived nutrients and challenges in in vitro cultivation. Validated with strong agreement to proteomics data, the model demonstrates high predictive reliability. Key insights include unique metabolic adaptations such as lactate uptake for ATP production and alternative redox-balancing mechanisms. These findings provide a robust framework for future studies aimed at unraveling the pathogen's survival strategies and identifying potential metabolic vulnerabilities.

Horizontal acquisition of prokaryotic hopanoid biosynthesis reorganizes membrane physiology driving lifestyle innovation in a eukaryote

Horizontal gene transfer is a source of metabolic innovation and adaptation to new environments. How new metabolic functionalities are integrated into host cell biology is largely unknown. Here, we probe this fundamental question using the fission yeast Schizosaccharomyces japonicus, which has acquired a squalene-hopene cyclase Shc1 through horizontal gene transfer. We show that Shc1-dependent production of hopanoids, mimics of eukaryotic sterols, allows S. japonicus to thrive in anoxia, where sterol biosynthesis is not possible. We demonstrate that glycerophospholipid fatty acyl asymmetry, prevalent in S. japonicus, is crucial for accommodating both sterols and hopanoids in membranes and explain how Shc1 functions alongside the sterol biosynthetic pathway to support membrane properties. Reengineering experiments in the sister species S. pombe show that hopanoids entail new traits in a naïve organism, but the acquisition of a new enzyme may trigger profound reorganization of the host metabolism and physiology.