Respiratory Chain Research Articles

Gasdermin D Mediated Mitochondrial Metabolism Orchestrate Neurogenesis Through LDHA During Embryonic Development.

Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD-mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism-like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC-1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF-𝜿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism.

Reduced diffusional limitations in carnation stems facilitate higher photosynthetic rates and reduced photorespiratory losses compared with leaves.

Green stem photosynthesis has been shown to be relatively inefficient but can occasionally contribute significantly to the carbon budget of desert plants. Although the possession of green photosynthetic stems is a common trait, little is known about their photosynthetic characteristics in non-desert species. Dianthus caryophyllus is a semi-woody species with prominent green stems, which show similar photosynthetic anatomy with leaves. In the present study, we used a combination of gas exchange and chlorophyll fluorescence measurements, some of which were taken under varying O2 and CO2 partial pressures, to investigate whether the apparent anatomical similarities between the species' leaves and stems translate into similar photosynthetic physiology and capacity for CO2 assimilation. Both organs displayed high photosynthetic electron transport rates (ETR) and similar values of steady-state non-photochemical quenching (NPQ), albeit leaves could attain them faster. The analysis of OJIP transients showed that the quantum efficiencies and energy fluxes along the photosynthetic electron transport chain are largely similar between leaves and stems. Stems displayed higher total conductance to CO2 diffusion, similar biochemical properties, significantly higher photosynthetic rates and lower water use efficiency than leaves. Leaf ETR was more sensitive to sub-ambient O2 and super-ambient CO2 partial pressures, while leaves also displayed a higher relative rate of Rubisco oxygenation. We conclude that the highly responsive NPQ and the enhanced photorespiration and WUE in leaves represent photoprotective and water-conserving adaptations to the high incident light intensities they experience naturally, at the expense of higher CO2 assimilation rates, which the vertically orientated stems can readily attain.

Stereotactically intracerebral transplantation of neural stem cells for ischemic stroke attenuated inflammatory responses and promoted neurogenesis: an experimental study with monkeys.

Ischemic stroke is a common neurovascular disorder with high morbidity and mortality. However, the underlying mechanism of stereotactically intracerebral transplantation of human neural stem cells (hNSCs) is not well elucidated. Four days after ischemic stroke induced by Rose Bengal photothrombosis, seven cynomolgus monkeys were transplanted with hNSCs or vehicles stereotactically and followed up for 84 days. Behavioral assessments, magnetic resonance imaging, blood tests, and pathological analysis were performed before and after treatment. The proteome profiles of the left and right precentral gyrus and hippocampus were evaluated. Extracellular vesicle micro-RNA (miRNA) from the peripheral blood was extracted and analyzed. hNSC transplantation reduced the remaining infarcted lesion volume of cynomolgus monkeys with ischemic stroke without remarkable side effects. Proteomic analyses indicated that hNSC transplantation promoted GABAergic and glutamatergic neurogenesis and restored the mitochondrial electron transport chain function in the ischemic infarcted left precentral gyrus or hippocampus. Immunohistochemical staining and quantitative real-time reverse transcription PCR confirmed the promoting effects on neurogenesis and revealed that hNSCs attenuated post-infarct inflammatory responses by suppressing resident glia activation and mediating peripheral immune cell infiltration. Consistently, miRNA-sequencing revealed the miRNAs that were related to these pathways were downregulated after hNSC transplantation. This study indicates that hNSCs can be effectively and safely used to treat ischemic stroke by promoting neurogenesis, regulating post-infarct inflammatory responses, and restoring mitochondrial function in both the infarct region and hippocampus.

Illusory movements for immobile patients with extensive burns (IMMOBILE): A randomized, controlled, cross-over trial

IntroductionPatients who have sustained extensive burns frequently exhibit substantial damage to skeletal muscle and associated complications. The rehabilitation of these patients can be challenging due to the nature of the injury and the subsequent complications. Nevertheless, there is a possibility that functional proprioceptive stimulation (illusory movements) may facilitate effective rehabilitation in patients with limited physiotherapy options. Nevertheless, this approach has yet to be tested in patients with burn injuries. Material and methodologyA prospective, randomised, crossover trial was conducted at a burn centre in a tertiary teaching hospital. The objective was to assess the effects of illusory movements on energy metabolism, insulin sensitivity, and skeletal muscle biology in adult critically ill patients with deep burns covering 30 % or more of the total body surface area. Two 30-minute daily sessions of functional proprioceptive stimulation were administered in addition to the standard physical therapy or physical activity regimen. Subsequently, the patients proceeded to the next stage of the trial, which involved a two-week crossover period. Measurements and main resultsDaily indirect calorimetry and calculation of nitrogen balance. Skeletal muscle biopsies from vastus lateralis for high resolution respirometry and euglycemic clamps to assess whole body glucose disposal were performed three times: at baseline and then fortnightly after each intervention period. The intervention was feasible and well tolerated in both early and late stages of burn disease. It did not change energy expenditure (mean change −33 [95 % CI: −292;+227] kcal .24 h−1, p = 0.79), nitrogen balance (+2.0 [95 % CI: −3.1;+7.1] g N .1.73 m−2 BSA .24 h−1), or insulin sensitivity (mean change of insulin-mediated glucose disposal −0.33 [95 % CI: −1.18;+0.53] mmol.h−1). At the cellular level, the intervention increased the capacity of mitochondria to synthesize ATP by aerobic phosphorylation and tended to increase mitochondrial coupling. Functional capacities of fatty acid oxidation and electron transfer chain complexes I, II, and IV were unaffected. ConclusionsCompared to physical therapy alone, two daily sessions of functional proprioceptive stimulation in addition to usual physical therapy in patients with extensive burns did not change energy expenditure, insulin sensitivity, nitrogen balance, or energy substrate oxidation. At cellular level, the intervention improved the capacity of aerobic phosphorylation in skeletal muscle mitochondria. Clinical effects remain to be demonstrated in adequately powered trials.

Carbon Steel Corrosion Induced by Sulfate-Reducing Bacteria: A Review of Electrochemical Mechanisms and Pathways in Biofilms

Microbial metal corrosion has become an important topic in metal research, which is one of the main causes of equipment damage, energy loss, and economic loss. At present, the research on microbial metal corrosion focuses on the characteristics of corrosion products, the environmental conditions affecting corrosion, and the measures and means of corrosion prevention, etc. In contrast, the main microbial taxa involved in metal corrosion, their specific role in the corrosion process, and the electron transfer pathway research are relatively small. This paper summarizes the mechanism of microbial carbon steel corrosion caused by SRB, including the cathodic depolarization theory, acid metabolite corrosion theory, and the biocatalytic cathodic sulfate reduction mechanism. Based on the reversible nature of electron transfer in biofilms and the fact that electrons must pass through the extracellular polymers layer between the solid electrode and the cell, this paper focuses on three types of electrochemical mechanisms and electron transfer modes of extracellular electron transfer occurring in microbial fuel cells, including direct-contact electron transfer, electron transfer by conductive bacterial hair proteins or nanowires, and electron shuttling mediated by the use of soluble electron mediators. Finally, a more complete pathway of electron transfer in microbial carbon steel corrosion due to SRB is presented: an electron goes from the metal anode, through the extracellular polymer layer, the extracellular membrane, the periplasm, and the intracellular membrane, to reach the cytoplasm for sulfate allosteric reduction. This article also focuses on a variety of complex components in the extracellular polymer layer, such as extracellular DNA, quinoline humic acid, iron sulfide (FeSX), Fe3+, etc., which may act as an extracellular electron donor to provide electrons for the SRB intracellular electron transfer chain; the bioinduced mineralization that occurs in the SRB biofilm can inhibit metal corrosion, and it can be used for the development of green corrosion inhibitors. This provides theoretical guidance for the diagnosis, prediction, and prevention of microbial metal corrosion.

N6-methyladenosine modification of SLC38A7 promotes cell migration, invasion, oxidative phosphorylation, and mitochondrial function in gastric cancer

Solute carrier (SLC) 38 family responsible for trans-membrane transport of neutral amino acids, plays a role in the proliferation, invasion, and metastasis of cancer cells, but its role in gastric cancer (GC) progression remains unclear. This study aimed to explore the biological effects of SLC38A7 and its regulatory mechanisms in GC. RNA expression data, tumor tissue specimens, and GC cell lines were used for bioinformatics and experimental analyses. Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay were used to evaluate cell viability, migration, and invasion, respectively. Oxidative phosphorylation, mitochondrial membrane potential and expression of the critical proteins in the mitochondrial respiratory chain were assayed using extracellular flux analysis, flow cytometry, and Western blot, respectively. RNA immunoprecipitation assay was used to explore the mechanisms of N6-methyladenosine (m6A) methylation. SLC38A7 was upregulated in GC tissue and cell lines. SLC38A7 silencing suppressed cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in cancer cells. SLC38A7 overexpression had the opposite biological effects. Interactions between SLC38A7 and methyltransferase like 3 (METTL3) or insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were detected. SLC38A7 mRNA stability was maintained by METTL3/IGF2BP2 axis in an m6A-dependent manner. Our results suggest that SLC38A7, stabilized by METTL3 and IGF2BP2-mediated m6A methylation, enhances cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in GC, highlighting its role as a potential therapeutic target for GC.

Abstract P194: Metabolic effects of GDF15 and Activin A on trophoblasts

Preeclampsia (PE), a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality. The pathophysiology is not fully elucidated. Activin A and GDF15 are part of the TGFβ superfamily and markers for trophoblast differentiation. Both are senescence associated secretory phenotype (SASP) factors that have been associated with cardiovascular disease. Mitochondrial dysfunction is associated with SASP and both have been described in PE. Serum levels of GDF15 and Activin A, were elevated in the maternal blood prior to the onset of PE and found to be elevated in placental tissue of women with PE. BeWo cells were metabolically reprogrammed to a physiological glucose-environment by cultivating them for 10-15 passages in a cell culture medium with 5.5 mM glucose as opposed to the standard high-glucose environment at 17.1mM. Next, BeWo cells were differentiated into multinucleated syncytiotrophoblasts with Forskolin, and with DMSO as solvent control to model cytotrophoblasts. Subsequently, these two trophoblast differentiation states were treated with GDF15 (20 ng/ml) and Activin A (20ng/ml) and the cell metabolic profile was analyzed. Additionally, a single cell human trophoblast organoid transcriptomics dataset from Shannon et al. was investigated for expression patterns of GDF15 and INHBA (Activin A) together with the overall metabolic profile of trophoblast cells. Treating BeWo cells with Activin A and GDF15 leads to an increase in mitochondrial activity, shown by elevated ATP levels in syncytiotrophoblast and an increase in mitochondrial membrane potential in cytotrophoblasts. Additionally, the oxygen consumption rate is significantly higher in syncytiotrophoblasts after Activin A and GDF15 treatment. In human trophoblast organoids, syncytiotrophoblasts showed the lowest metabolic activity measured by the expression of genes related to glycolysis and mitochondrial respiratory chain. Furthermore, GDF15 and INHBA (Activin A) were strongly expressed in syncytiotrophoblasts. Together, Activin A and GDF15 stimulation increases the metabolic activity in BeWo cells. As preeclampsia is associated with mitochondrial dysfunction as well as with senescence, our data indicate a potential role of Activin A and GDF15 in preeclampsia development.

Improved fermentative gamma-aminobutyric acid production from glucose by the inactivation of respiratory chain components NDH-I and Cytbo₃ in Escherichia coli

Gamma-aminobutyric acid (GABA), which is synthesized from l-glutamic acid via glutamate decarboxylase (Gad), is used as food, supplements, and biodegradable plastics. Our previous study demonstrated an Escherichia coli mutant (ΔΔ) strain, lacking type I NADH dehydrogenase (NDH-I) and cytochrome bo3 oxidase (Cytbo3), produced 7g/L glutamic acid on MS1 glucose-minimal medium. In this study, the ΔΔ strain was used for improving GABA production. A plasmid (pMBL19-gadB') expressing a mutated E.coli GadB (Glu89Gln/Δ452-466), retaining activity at neutral pH, was introduced into the ΔΔ strain and its parent strain (W1485). The ΔΔ strain carrying pMBL19-gadB' exhibited a twofold increase in GABA production compared to the W1485 strain carrying pMBL19-gadB'. Deleting the C-terminal (Δ471-511) of GadC antiporter in the ΔΔ strain further improved GABA yield by 1.5g/L when cultured in MS1 glucose-minimal medium. On the other hand, a large amount of glutamic acid produced by the ΔΔ strain was not fully converted to GABA, likely due to the inhibition of GadB activity by the accumulation of acetic acid. Although there is room for improvement, these results indicate the efficacy of the ΔNDH-IΔCytbo3 double mutation in augmenting GABA production.

RNA sequencing reveals transcriptomic changes in PC-12 cells following plasminogen activator, tissue type overexpression.

Pheochromocytoma and paraganglioma, collectively known as PPGL, are categorized as neuroendocrine tumors with the potential for malignancy. Plasminogen activator, tissue type (PLAT) is a protein encoding gene that encodes tissue-type plasminogen activator, which converts plasminogen to plasmin. There is limited research on the association between PLAT and PPGL. Previous studies have only found that the expression level of PLAT protein is significantly increased in PPGL with deficient blood supply, and its role in the occurrence and progression of PPGL remains unclear and needs further clarification. The purpose of this study is to provide some new clues to elucidate the role of PLAT in PPGL, in order to better guide future research directions. The PC-12 cell line was selected for this study, and lentivirus transfection technology was used to construct control and PLAT overexpression cell models. Transcriptomic information of PLAT regulation in PC-12 cells was obtained through RNA sequencing, and differentially expressed genes (DEGs) were screened using bioinformatics methods. The physiological functions and related signaling pathways of these genes were analyzed. After validating the overexpression cell model and performing quality control analysis on the transcriptome sequencing data, DEGs were identified. The Gene Ontology (GO) functional enrichment analysis of DEGs revealed significant enrichment in 46 GO functions, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed significant enrichment in seven pathways. It was found that these genes were significantly enriched in functional pathways associated with mitochondrial respiratory chain and energy metabolism. This study provides some insights into the role of PLAT in pheochromocytoma and suggests directions for further research on its involvement in tumor development and angiogenesis. However, the specific regulatory mechanisms still require further validation.

CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.

Metabolic evolution and bottleneck insights into simultaneous autotroph-heterotroph anammox system for real municipal wastewater nitrogen removal

When biological nitrogen removal (BNR) systems shifted from treating simulated wastewater to real wastewater, a microbial succession occurred, often resulting in a decline in efficacy. Notably, despite their high nitrogen removal efficiency for real wastewater, anammox coupled systems operating without or with minimal carbon sources also exhibited a certain degree of performance reduction. The underlying reasons and metabolic shifts within these systems remained elusive. In this study, the simultaneous autotrophic/heterotrophic anammox system demonstrated remarkable metabolic resilience upon exposure to real municipal wastewater, achieving a nitrogen removal efficiency (NRE) of 82.83 ± 2.29 %. This resilience was attributed to the successful microbial succession and the complementary metabolic functions of heterotrophic microorganisms, which fostered a resilient microbial community. The system's ability to harness multiple electron sources, including NADH oxidation, the TCA cycle, and organics metabolism, allowed it to establish a stable and efficient electron transfer chain, ensuring effective nitrogen removal. Despite the denitrification channel's nitrite supply capability, the analysis of the interspecies correlation network revealed that the synergistic metabolism between AOB and AnAOB was not fully restored, resulting in selective functional bacterial and genetic interactions and the system's PN/A performance declined. Additionally, the enhanced electron affinity of PD increased interconversion of NO3−-N and NO2−-N, limiting the efficient utilization of electrons and thereby constraining nitrogen removal performance. This study elucidated the metabolic mechanism of nitrogen removal limitations in anammox-based systems treating real municipal wastewater, enhancing our understanding of the metabolic functions and electron transfer within the symbiotic bacterial community.

Prenylated xanthones from mangosteen (Garcinia mangostana) target oxidative mitochondrial respiration in cancer cells

Mangosteen (Garcinia mangostana) is well-known for its nutritional value and health benefits. Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Here we show that the prenylated xanthones, α-mangostin, γ-mangostin, 9-hydroxycalabaxanthone (9-HCX), and garcinone E from the mangosteen pericarp exhibit cytotoxicity against a panel of human cancer cell lines including lung adenocarcinoma (A549), cervical carcinoma (HeLa), prostatic carcinoma (DU 145), pancreatic carcinoma (MIA PaCa-2), hepatocellular carcinoma (Hep G2), bladder urothelial cancer (5637), as well as the triple-negative breast cancer cells MDA-MB-231. In line with its higher predicted bioactivity score compared to other prenylated xanthones, 9-HCX induced the strongest antiproliferative and proapoptotic effects in MDA-MB-231 breast cancer xenografts in vivo. In different in vitro models, we demonstrate that prenylated xanthones from G. mangostana target mitochondria in cancer cells by inhibition of the mitochondrial respiratory chain complex II (α-mangostin, γ-mangostin, and garcinone E) and complex III (9-HCX) as shown in isolated mitochondria. Accordingly, oxidative mitochondrial respiration (OXPHOS) was inhibited, mitochondrial proton leak increased, and adenosine triphosphate (ATP) synthesis decreased as analyzed by Seahorse assay in MDA-MB-231 cells. Hence, the prenylated xanthones increased mitochondrial superoxide levels, induced mitochondrial membrane permeabilization, and initiated caspase 3/7-mediated apoptosis in MDA-MB-231 triple-negative breast cancer cells. Thus, prenylated xanthones from Garcinia mangostana exhibit anticancer activity based on interference with the mitochondrial respiration.

Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma.

mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS.

Translational Cardiology: Practical Insights into the Coenzyme Q10 Role as Potential Therapeutic Agent for Cardiovascular Disease Treatment via Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background and Objectives: As clinicians seek novel treatment strategies for CVDs, personalized nutrient recommendations are becoming essential. CoQ10, a key component of the mitochondrial electron transport chain, shows promise with proven cardioprotective effects. This systematic review and meta-analysis evaluates the efficacy of CoQ10 supplementation in improving mitochondrial function, systolic performance, and other parameters in CVD. Methods: Analysis included data from PubMed, Embase, and the Cochrane Library up to January 2024. It focused on randomized controlled trials (RCTs) involving adults with cardiovascular diseases (CVDs), comparing CoQ10 with placebo or standard care. Data extraction and quality assessment followed PRISMA guidelines, the Cochrane Collaboration's RoB2 tool, AMSTAR 2, and GRADE. The primary outcome was mitochondrial function (ATP production, respiratory capacity), and the secondary outcome was systolic function (ejection fraction). Findings: CoQ10 supplementation improved ejection fraction (mean difference: 5.6%, 95% CI: 3.2% to 8.0%, p<0.001, I²=25%). The I² statistic for ejection fraction was 25%, indicating low heterogeneity. Mitochondrial function showed increased ATP production (SMD: 0.82, 95% CI: 0.60 to 1.04, p<0.001, I²=30%) and enhanced respiratory capacity (SMD: 0.75, 95% CI: 0.53 to 0.97, p<0.001, I²=28%). The I² statistics for ATP production and mitochondrial respiratory capacity were 30% and 28%, respectively, suggesting low to moderate heterogeneity. Sensitivity analyses confirmed the robustness of the results, with consistent effect sizes and confidence intervals across both fixed-effect and random-effects models, and no significant changes upon excluding high-risk studies. Publication bias was low, as indicated by funnel plots and Egger's test (p=0.12). Limitations: Larger-scale RCTs are needed to confirm findings and determine the optimal dosage and duration of CoQ10 therapy. Conclusion: CoQ10 has been consistently shown to improve mitochondrial function, systolic performance, and other key cardiovascular health parameters in CVD patients. The evidence here presented strongly bridges the gaps between the current research and clinical applications and supports clinicians in implementing the prescription of CoQ10 supplementation as an intervention evidence-based therapeutic agent that effectively improves cardiovascular health outcomes

Exploring Evolutionary Pathways and Abiotic Stress Responses through Genome-Wide Identification and Analysis of the Alternative Oxidase (AOX) Gene Family in Common Oat (Avena sativa).

The alternative oxidase (AOX), a common terminal oxidase in the electron transfer chain (ETC) of plants, plays a crucial role in stress resilience and plant growth and development. Oat (Avena sativa), an important crop with high nutritional value, has not been comprehensively studied regarding the AsAOX gene family. Therefore, this study explored the responses and potential functions of the AsAOX gene family to various abiotic stresses and their potential evolutionary pathways. Additionally, we conducted a genome-wide analysis to explore the evolutionary conservation and divergence of AOX gene families among three Avena species (Avena sativa, Avena insularis, Avena longiglumis) and four Poaceae species (Avena sativa, Oryza sativa, Triticum aestivum, and Brachypodium distachyon). We identified 12 AsAOX, 9 AiAOX, and 4 AlAOX gene family members. Phylogenetic, motif, domain, gene structure, and selective pressure analyses revealed that most AsAOXs, AiAOXs, and AlAOXs are evolutionarily conserved. We also identified 16 AsAOX segmental duplication pairs, suggesting that segmental duplication may have contributed to the expansion of the AsAOX gene family, potentially preserving these genes through subfunctionalization. Chromosome polyploidization, gene structural variations, and gene fragment recombination likely contributed to the evolution and expansion of the AsAOX gene family as well. Additionally, we hypothesize that AsAOX2 may have potential function in resisting wounding and heat stresses, while AsAOX4 could be specifically involved in mitigating wounding stress. AsAOX11 might contribute to resistance against chromium and waterlogging stresses. AsAOX8 may have potential fuction in mitigating ABA-mediated stress. AsAOX12 and AsAOX5 are most likely to have potential function in mitigating salt and drought stresses, respectively. This study elucidates the potential evolutionary pathways of the AsAOXs gene family, explores their responses and potential functions to various abiotic stresses, identifies potential candidate genes for future functional studies, and facilitates molecular breeding applications in A. sativa.

Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis

BackgroundTransport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and...

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells

Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60–70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells.Key messagesTRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours.TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells.TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O2 Reduction.

Fusobacterium nucleatum, a Gram-negative obligate anaerobe, is common to the oral microbiota, but the species is known to infect other sites of the body where it is associated with a range of pathologies. At present, little is known about the mechanisms by which F. nucleatum mitigates against oxidative and nitrosative stress. Inspection of the F. nucleatum subsp. polymorphum ATCC 10953 genome reveals that it encodes a flavodiiron protein (FDP; FNP2073) that is known in other organisms to reduce NO to N2O and/or O2 to H2O. FNP2073 is dicistronic with a gene encoding a multicomponent enzyme termed BCR for butyryl-CoA reductase. BCR is composed of a butyryl-CoA dehydrogenase domain (BCD), the C-terminal domain of the α-subunit of the electron-transfer flavoprotein (Etfα), and a rubredoxin domain. We show that BCR and the FDP form an α4β4 heterotetramic complex and use butyryl-CoA to selectively reduce O2 to H2O. The FAD associated with the Etfα domain (α-FAD) forms red anionic semiquinone (FAD•-), whereas the FAD present in the BCD domain (δ-FAD) forms the blue-neutral semiquinone (FADH•), indicating that both cofactors participate in one-electron transfers. This was confirmed in stopped-flow studies where the reduction of oxidized BCR with an excess of butyryl-CoA resulted in rapid (<1.6 ms) interflavin electron transfer evidenced by the formation of the FAD•-. Analysis of bacterial genomes revealed that the dicistron is present in obligate anaerobic gut bacteria considered to be beneficial by virtue of their ability to produce butyrate. Thus, BCR-FDP may help to maintain anaerobiosis in the colon.

Association of mutations in Mycobacterium tuberculosis complex (MTBC) respiration chain genes with hyper-transmission

BackgroundThe respiratory chain plays a key role in the growth of Mycobacterium tuberculosis complex (MTBC). However, the exact regulatory mechanisms of this system still need to be elucidated, and only a few studies have investigated the impact of genetic mutations within the respiratory chain on MTBC transmission. This study aims to explore the impact of respiratory chain gene mutations on the global spread of MTBC.ResultsA total of 13,402 isolates of MTBC were included in this study. The majority of the isolates (n = 6,382, 47.62%) belonged to lineage 4, followed by lineage 2 (n = 5,123, 38.23%). Our findings revealed significant associations between Single Nucleotide Polymorphisms (SNPs) of specific genes and transmission clusters. These SNPs include Rv0087 (hycE, G178T), Rv1307 (atpH, C650T), Rv2195 (qcrA, G181C), Rv2196 (qcrB, G1250T), Rv3145 (nuoA, C35T), Rv3149 (nuoE, G121C), Rv3150 (nuoF, G700A), Rv3151 (nuoG, A1810G), Rv3152 (nuoH, G493A), and Rv3157 (nuoM, A1243G). Furthermore, our results showed that the SNPs of atpH C73G, atpA G271C, qcrA G181C, nuoJ G115A, nuoM G772A, and nuoN G1084T were positively correlated with cross-country transmission clades and cross-regional transmission clades.ConclusionsOur study uncovered an association between mutations in respiratory chain genes and the transmission of MTBC. This important finding provides new insights for future research and will help to further explore new mechanisms of MTBC pathogenicity. By uncovering this association, we gain a more complete understanding of the processes by which MTBC increases virulence and spread, providing potential targets and strategies for preventing and treating tuberculosis.

Misprogramming of glucose metabolism impairs recovery of hippocampal slices from neuronal GLT-1 knockout mice and contributes to excitotoxic injury through mitochondrial superoxide production.

We have previously reported a failure of recovery of synaptic function in the CA1 region of acute hippocampal slices from mice with a conditional neuronal knockout (KO) of GLT-1 (EAAT2, Slc1A2) driven by synapsin-Cre (synGLT-1 KO). The failure of recovery of synaptic function is due to excitotoxic injury. We hypothesized that changes in mitochondrial metabolism contribute to the heightened vulnerability to excitotoxicity in the synGLT-1 KO mice. We found impaired flux of carbon from 13C-glucose into the tricarboxylic acid cycle in synGLT-1 KO cortical and hippocampal slices compared with wild-type (WT) slices. In addition, we found downregulation of the neuronal glucose transporter GLUT3 in both genotypes. Flux of carbon from [1,2-13C]acetate, thought to be astrocyte-specific, was increased in the synGLT-KO hippocampal slices but not cortical slices. Glycogen stores, predominantly localized to astrocytes, are rapidly depleted in slices after cutting, and are replenished during exvivo incubation. In the synGLT-1 KO, replenishment of glycogen stores during exvivo incubation was compromised. These results suggest both neuronal and astrocytic metabolic perturbations in the synGLT-1 KO slices. Supplementing incubation medium during recovery with 20 mM D-glucose normalized glycogen replenishment but had no effect on recovery of synaptic function. In contrast, 20 mM non-metabolizable L-glucose substantially improved recovery of synaptic function, suggesting that D-glucose metabolism contributes to the excitotoxic injury in the synGLT-1 KO slices. L-lactate substitution for D-glucose did not promote recovery of synaptic function, implicating mitochondrial metabolism. Consistent with this hypothesis, phosphorylation of pyruvate dehydrogenase, which decreases enzyme activity, was increased in WT slices during the recovery period, but not in synGLT-1 KO slices. Since metabolism of glucose by the mitochondrial electron transport chain is associated with superoxide production, we tested the effect of drugs that scavenge and prevent superoxide production. The superoxide dismutase/catalase mimic EUK-134 conferred complete protection and full recovery of synaptic function. A site-specific inhibitor of complex III superoxide production, S3QEL-2, was also protective, but inhibitors of NADPH oxidase were not. In summary, we find that the failure of recovery of synaptic function in hippocampal slices from the synGLT-1 KO mouse, previously shown to be due to excitotoxic injury, is caused by production of superoxide by mitochondrial metabolism.