Search Results (4,365)

The introduction of new sequencing approaches into clinical practice has radically changed the diagnostic approach to mitochondrial diseases, significantly improving the molecular definition rate in this group of neurogenetic disorders. At the same time, there have been no equal successes in the area of in-depth understanding of disease mechanisms and few innovative therapeutic approaches have been proposed recently. In this regard, the identification of the molecular basis of phenotypic variability in primary mitochondrial disorders represents a key aspect for deciphering disease mechanisms with important therapeutic implications. In this study, we present data from proteomic investigations in two subjects affected by mitochondrial disease characterized by a different clinical severity and associated with the same variant in the TWNK gene, encoding the mitochondrial DNA and RNA helicase with a specific role in the mtDNA replisome. Heterozygous pathogenic variants in this gene are associated with progressive external ophthalmoplegia and ptosis, usually with adult onset. The overall results suggest an imbalance in glucose metabolism and ROS production/regulation, with possible consequences on the phenotypic manifestations of the enrolled subjects. Although the data will need to be validated in a large cohort, proteomic investigations have proven to be a valid approach for a deep understanding of these neurometabolic disorders. Full article

The high-risk Human Papillomavirus (HR-HPV) is the causal agent of different human cancers such as cervical, vulvar, and oropharynx cancer. This is because persistent HR-HPV infection alters several cellular processes involved in cell proliferation, apoptosis, immune evasion, genomic instability, and cellular transformation. The above is mainly due to the expression of early expression proteins of HR-HPV, which interact and alter these processes. HR-HPV proteins have even been shown to regulate redox state and mitochondrial metabolism, which has been suggested as a risk factor for cancer development. Redox state refers to a balance between reactive oxygen species (ROS) and antioxidants. Although ROS regulates cell signaling, high levels of ROS generate oxidative stress (OS). OS promotes damage to DNA, proteins, carbohydrates, and lipids, which causes mutation accumulation and genome instability associated with cancer development. Thus, OS has been associated with the establishment and development of different types of cancer and has recently been proposed as a cofactor in HR-HPV-associated cancers. However, OS also induces cell death, which can be used as a target for different molecules, such as phytochemicals. Furthermore, phytochemicals target HPV oncoproteins E6 and E7, causing their degradation. Because phytochemicals could induce OS and target HPV oncoproteins, we hypothesize that these compounds induce cell death in HPV-associated cancers. Since the redox state is crucial in developing, establishing, and clearing HR-HPV-associated cancer, this review focuses on evidence for using phytochemicals as therapeutic agents that target HPV proteins and the redox state to induce the elimination of HPV-related cancers. Full article

Candida albicans (C. albicans) is a main cause of hospital-acquired fungal infections. Combination therapy is promising as a novel anti-C. albicans strategy because of its better efficacy. Theasaponins are pentacyclic triterpenes in the Camellia genus with multiple biological activities. Our previous studies prove that theasaponins display inhibitory activity against C. albicans. Ascorbic acid (VC) is a vitamin found in many plants that shows potential in combination therapy. However, whether VC enhances the activity of theasaponins remains unclear. In this study, the checkerboard micro-dilution method was used to assess the effect of VC (0–80 mmol/L) on the anti-C. albicans effect of theasaponins (0–1000 μg/mL). Then, the effects of theasaponins (31.25 μg/mL), VC (80 mmol/L), and theasaponins (31.25 μg/mL) + VC (80 mmol/L) on C. albicans planktonic cells and different stages of biofilm formation were assessed. Transcriptomic analysis was conducted to investigate the molecular mechanisms. According to the results, VC enhanced the anti-planktonic and anti-biofilm effect of theasaponins against C. albicans. The minimum inhibitory concentration of theasaponins was significantly decreased and the fungicidal efficiency was increased with the addition of VC. VC remarkably aggravated the suppression of theasaponins with regard to various virulence factors of C. albicans, including adhesion, early biofilm formation, mature biofilm, cell surface hydrophobicity, and phospholipase activity. Compared with the theasaponins or VC groups, the level of intracellular reactive oxygen species was higher, while the levels of mitochondrial membrane potential and adenosine triphosphate were lower in the combination group, suggesting more severe oxidative stress, mitochondrial injury, and energy deficiency. Transcriptomic analysis revealed that the combination predominantly suppressed the pathways of glycolysis, glycerophospholipid metabolism, glutathione metabolism, and cysteine and methionine metabolism. This implied that energy deficiency and redox imbalance were associated with the anti-C. albicans activity of the combination. These results prove that VC enhances the inhibitory effect of theasaponins against C. albicans and that the combination has the potential to be used as a topical antifungal therapy or disinfectant. Full article

Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., glucose) from T cells, leading to T-cell dysfunction and leukemia progression. Methods: Thus, we explored whether genetic reprogramming of T-cell metabolism could improve their survival and empower T cells with a competitive glucose-uptake advantage against blasts and inhibit their uncontrolled proliferation. Results: Here, we discovered that high-glucose concentration reduced the T-cell expression of glucose transporter GLUT1 (SLC2A1) and TFAM (mitochondrion transcription factor A), an essential transcriptional regulator of mitochondrial biogenesis, leading to their impaired expansion ex vivo. To overcome the glucose-induced genetic deficiency in metabolism, we engineered T cells with lentiviral overexpression of SLC2A1 and/or TFAM transgene. Multi-omics analyses revealed that metabolic reprogramming promoted T-cell proliferation by increasing IL-2 release and reducing exhaustion. Moreover, the engineered T cells competitively deprived glucose from allogenic blasts and lessened leukemia burden in vitro. Conclusions: Our findings propose a novel T-cell immunotherapy that utilizes a dual strategy of starving blasts and cytotoxicity for preventing uncontrolled leukemia proliferation. Full article

Continual climate change strongly influences temperature conditions worldwide, making ectothermic animals as suitable species for studying the potential impact of climate change on global biodiversity. However, the study of how lizards distributed at different latitudes respond to climate change at the transcriptome level is still insufficient. According to the Climatic Variability Hypothesis (CVH), the range of climate fluctuations experienced by terrestrial animals throughout the year increases with latitude, so individuals at higher latitudes should exhibit greater thermal plasticity to cope with fluctuating environments. Mitochondria, as the energy center of vertebrate cells, may indicate species’ plasticity through the sensitivity of gene expression. In this study, we focused on the changes in transcript levels of liver mitochondrial protein-coding genes (PCGs) in skinks from the genus Plestiodon (P. capito and P. elegans) and the genus Scincella (S. modesta and S. reevesii) under low-temperature conditions of 8 °C, compared to the control group at 25 °C. Species within the same genus of skinks exhibit different latitudinal distribution patterns. We found that the two Plestiodon species, P. elegans and P. capito, employ a metabolic depression strategy (decreased transcript levels) to cope with low temperatures. In contrast, the two Scincella species show markedly different patterns: S. modesta exhibits significant increases in the transcript levels of six genes (metabolic compensation), while in S. reevesii, only two mitochondrial genes are downregulated (metabolic depression) compared to the control group. We also found that P. capito and S. modesta, which live at mid-to-high latitudes, exhibit stronger adaptive responses and plasticity at the mitochondrial gene level compared to P. elegans and S. reevesii, which live at lower latitudes. We suggest that this enhanced adaptability corresponds to more significant changes in a greater number of genes (plasticity genes). Full article

Copper is a vital trace element in oxidized and reduced forms. It plays crucial roles in numerous biological events such as redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy, and immune modulation. Maintaining the balance of copper in the body is essential because its deficiency and excess can be harmful. Abnormal copper metabolism has a two-fold impact on the development of tumors and cancer treatment. Cuproptosis is a form of cell death that occurs when there is excessive copper in the body, leading to proteotoxic stress and the activation of a specific pathway in the mitochondria. Research has been conducted on the advantageous role of copper ionophores and chelators in cancer management. This review presents recent progress in understanding copper metabolism, cuproptosis, and the molecular mechanisms involved in using copper for targeted therapy in cervical cancer. Integrating trace metals and minerals into nanoparticulate systems is a promising approach for controlling invasive tumors. Therefore, we have also included a concise overview of copper nanoformulations targeting cervical cancer cells. This review offers comprehensive insights into the correlation between cuproptosis-related genes and immune infiltration, as well as the prognosis of cervical cancer. These findings can be valuable for developing advanced clinical tools to enhance the detection and treatment of cervical cancer. Full article

As a component of circulating lipoproteins, APOE binds to cell surface receptors mediating lipoprotein metabolism and cholesterol transport. A growing body of evidence, including the identification of a broad variety of cellular proteins interacting with APOE, suggests additional independent functions. Investigating cellular localization and protein–protein interactions in cultured human hepatocytes, we aimed to contribute to the elucidation of hitherto unnoted cellular functions of APOE. We observed a strong accumulation of APOE in MAMs, equally evident for the two major isoforms APOE3 and APOE4. Using mass spectrometry proteome analyses, novel and previously noted APOE interactors were identified, including the mitochondrial proteins TOMM40, LONP1 and VDAC1. All three interactors were present in MAM fractions, which we think initially facilitates interactions with APOE. LONP1 is a protease with chaperone activity, which migrated to MAMs in response to ER stress, displaying a reinforced interaction with APOE. We therefore hypothesize that APOE may help in the unfolded protein response (UPR) by acting as a co-chaperone in cooperation with LONP1 at the interface of mitochondria and ER membranes. The interaction of APOE with the integral proteins TOMM40 and VDAC1 may point to the formation of bridging complexes connecting mitochondria with other organelles. Full article

Among the widespread trichothecene mycotoxins, T-2 toxin is considered the most toxic congener. In the present study, we utilized high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), coupled to the zebrafish (Danio rerio) embryo model, as a toxicometabolomics approach to elucidate the cellular, molecular and biochemical pathways associated with T-2 toxicity. Aligned with previous studies in the zebrafish embryo model, exposure to T-2 toxin was lethal in the high parts-per-billion (ppb) range, with a median lethal concentration (LC₅₀) of 105 ppb. Exposure to the toxins was, furthermore, associated with system-specific alterations in the production of reactive oxygen species (ROS), including decreased ROS production in the liver and increased ROS in the brain region, in the exposed embryos. Moreover, metabolic profiling based on HRMAS NMR revealed the modulation of numerous, interrelated metabolites, specifically including those associated with (1) phase I and II detoxification, and antioxidant pathways; (2) disruption of the phosphocholine lipids of cell membranes; (3) mitochondrial energy metabolism, including apparent disruption of the tricarboxylic acid (TCA) cycle, and the electron transport chain of oxidative phosphorylation, as well as “upstream” effects on carbohydrate, i.e., glucose metabolism; and (4) several compensatory catabolic pathways. Taken together, these observations enabled development of an integrated, system-level model of T-2 toxicity in relation to human and animal health. Full article

Background: Intense exercise leads to neutrophil extracellular traps (NETs) formation, which triggers cell disintegration. NET, as well as other processes of apoptosis, necrosis, and spontaneous secretion, result in increased levels of cell-free DNA (cf-DNA) in the circulation. An increment of cf-DNA is also observed in autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Repeated exhaustive exercises are an impulse for physiological adaptation; therefore, in this case–control study, we compared the exercise-induced increase in cf-DNA in men with T1DM and healthy controls to determine the development of the tolerance to exercise. Methods: Volunteers performed a treadmill run to exhaustion at a speed matching 70% of their personal VO2 max at three consecutive visits, separated by a 72 h resting period. Blood was collected before and after exercise for the determination of plasma cell-free nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Results: Each bout of exhaustive exercise induced a great elevation of cf n-DNA levels. An increase in cf mt-DNA was observed after each run. However, the significance of the increase was noted only after the second bout in T1DM participants (p < 0.02). Changes in cf-DNA concentration were transient and returned to baseline values during 72 h of resting. The exercise-induced increment in circulating cf n-DNA and cf mt-DNA was not significantly different between the studied groups (p > 0.05). Conclusions: Cf-DNA appears to be a sensitive marker of inflammation, with a lower post-exercise increase in individuals with T1DM than in healthy men. Full article

This paper discusses the cases of siblings that were born healthy, then diagnosed in their neonatal periods with cardiomyopathy and/or severe metabolic acidosis, which ran progressive courses and contributed to death in infancy. Molecular testing of the children confirmed the presence of an m.3303C>T point mutation in the mitochondrial DNA in the MT-TL1 gene, which was also present in their oligosymptomatic mother and their mother’s sister, an asymptomatic carrier. Full article

Objectives: To study the effects of all-trans retinoic acid (ATRA) on TGF-β2-induced effects of human retinal pigment epithelium cells under normoxia and hypoxia conditions. Methods: Two-dimensionally (2D) and three-dimensionally (3D) cultured ARPE19 cells were subjected to cellular functional analyses by transepithelial electrical resistance (TEER) and an extracellular flux assay (2D), measurement of levels of reactive oxygen species (ROS), gene expression analyses of COL1, αSMA, Zo-1, HIF1α, and PGC1α (2D), and physical property analyses (3D). Results: Under a normoxia condition, treatment with 100 nM ATRA substantially decreased barrier function regardless of the presence of 5 ng/mL TGF-β2 in 2D ARPE19 monolayer cells. Under a hypoxia condition, treatment with ATRA conversely increased barrier function, but the effect was masked by a marked increase in effects induced by TGF-β2. Although ATRA alone did not affect cellular metabolism and ROS levels in 2D ARPE cells, treatment with ATRA under a hypoxia condition did not affect ROS levels but shifted cellular metabolism from mitochondrial respiration to glycolysis. The changes of cellular metabolism and ROS levels were more pronounced with treatment of both ATRA and TGF-β2 independently of oxygen conditions. Changes in mRNA expressions of some of the above genes suggested the involvement of synergistical regulation of cellular functions by TGF-β2 and hypoxia. In 3D ARPE spheroids, the size was decreased and the stiffness was increased by either treatment with TGF-β2 or ATRA, but these changes were unexpectedly modulated by both ATRA and TGF-β2 treatment regardless of oxygen conditions. Conclusions: The findings reported herein indicate that TGF-β2 and hypoxia synergistically and differentially induce effects in 2D and 3D cultured ARPE19 cells and that their cellular properties are significantly altered by the presence of ATRA. Full article

The effects of methylmercury (MeHg) on exposed populations are a public health problem. In contrast to widely studied neurological damage, few cardiovascular changes have been described. Our group evaluated the cardiotoxicity of a cumulative dose of 70 mg.kg⁻¹ fractioned over a 14-day exposure period in mice (MeHg70 group). The effects of MeHg on proteins relevant to cardiac mitochondrial function were also investigated. The results obtained showed a reduction in oxygen consumption in the two settings. In cardiac tissue samples in oxygraphy studies, this reduction was related to a lower efficiency of complexes II and V, which belong to the oxidative phosphorylation system. In vivo, mice in the MeHg70 group presented lower oxygen consumption and running tolerance, as shown by ergometric analyses. Cardiac stress was evident in the MeHg70 group, as indicated by a marked increase in the level of the mRNA encoding atrial natriuretic peptide. Electrocardiogram studies revealed a lower heart rate at rest in the animals from the MeHg70 group, as well as prolonged left ventricular depolarisation and repolarisation. Through echocardiographic analysis, reductions in the left ventricular ejection fraction and left ventricular wall thickness of approximately 10% and 20%, respectively, were detected. These results indicate that the oral intake of MeHg can decrease cardiac function and oxidative metabolism. This finding highlights the importance of monitoring MeHg levels in humans and animals in contaminated areas, as well as periodically carrying out cardiac function tests. Full article

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by bones that are fragile and prone to breaking. The efficacy of existing therapies for OI is limited, and they are associated with potentially harmful side effects. OI is primarily due to a mutation of collagen type I and hence impairs bone regeneration. Mesenchymal stem cell (MSC) therapy is an attractive strategy to take advantage of the potential benefits of these multipotent stem cells to address the underlying molecular defects of OI by differentiating osteoblasts, paracrine effects, or immunomodulation. The maintenance of mitochondrial homeostasis is an essential component for improving the curative efficacy of MSCs in OI by affecting the differentiation, signaling, and immunomodulatory functions of MSCs. In this review, we highlight the MSC-based therapy pathway in OI and introduce the MSC regulation mechanism by mitochondrial homeostasis. Strategies aiming to modulate the metabolism and reduce the oxidative stress, as well as innovative strategies based on the use of compounds (resveratrol, NAD+, α-KG), antioxidants, and nanomaterials, are analyzed. These findings may enable the development of new strategies for the treatment of OI, ultimately resulting in improved patient outcomes. Full article

Iron plays a crucial role in various metabolic processes. However, the impact of 5-aminolevulinic acid (ALA) in combination with iron chelators on iron metabolism and the efficacy of ALA-photodynamic therapy (PDT) remain inadequately understood. This study aimed to examine the effect of thiosemicarbazone derivatives during ALA treatment on specific genes related to iron metabolism, with a particular emphasis on mitochondrial iron metabolism genes. In our study, we observed differences depending on the cell line studied. For the HCT116 and MCF-7 cell lines, in most cases, the decrease in the expression of selected targets correlated with the increase in protoporphyrin IX (PPIX) concentration and the observed photodynamic effect, aligning with existing literature data. The Hs683 cell line showed a different gene expression pattern, previously not described in the literature. In this study, we collected an extensive analysis of the gene variation occurring after the application of novel thiosemicarbazone derivatives and presented versatile and effective compounds with great potential for use in ALA-PDT. Full article

Isoorientin (ISO) is a natural lignan glycoside flavonoid found in various plants, including Charcot and Stonecrop. ISO exhibits diverse physiological and pharmacological effects, such as antioxidative, anti-inflammatory, hepatoprotective, antiviral, antianxiety, and anti-myocardial ischaemic properties, as well as lipid metabolism regulation. This study investigated the impact of ISO supplementation on oxidative stress and lipid accumulation in porcine early embryos, along with its underlying mechanisms. Porcine embryos were cultured in vitro under different concentrations of ISO (0, 1, 10, and 100 nM). The results revealed that 10 nM ISO significantly enhanced the blastocyst rate and total embryonic cell count in vitro. ISO-treated embryos exhibited reduced reactive oxygen species levels and elevated glutathione levels compared to the untreated group. In addition, ISO treatment significantly increased the expression of the key antioxidant regulator Nrf2, improved mitochondrial function, and reduced lipid droplet accumulation. Concurrently, early embryo autophagy and apoptosis levels decreased. Furthermore, ISO treatment upregulated antioxidant-related genes (SOD1, SOD2, and CAT) and mitochondrial biogenesis related genes (NRF1, NRF2, and SIRT1), while downregulating lipid synthesis-related genes (SREBP1 and FASN). Additionally, lipid hydrolysis-related genes (ACADS) were elevated. These findings collectively suggest that ISO may facilitate early embryonic development in pigs by ameliorating oxidative stress and lipid metabolism. Full article