Search Results (430)

Metabolic and cardiometabolic diseases are closely associated with mitochondrial dysfunction and redox imbalance. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2), a non-catalytic structural core subunit of mitochondrial respiratory chain Complex III, is increasingly recognized as a regulator of Complex III integrity, electron transfer, oxidative phosphorylation, and mitochondrial redox homeostasis. Under metabolic stress, reduced expression or functional impairment of UQCRC2 may promote electron leakage, mitochondrial reactive oxygen species (mtROS) generation, lipid peroxidation, impaired antioxidant defense, and disrupted glucose–lipid metabolism. These alterations may contribute to insulin resistance (IR), metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and cardiovascular disease (CVD). This review summarizes current evidence linking UQCRC2 dysfunction to mitochondrial bioenergetic failure, oxidative stress, inflammatory signaling, and cardiometabolic injury. We further discuss redox-regulatory pathways, including Nrf2, AMPK–SIRT1–PGC-1α, glutathione metabolism, and mitophagy, as well as pharmacological agents and natural compounds that may modulate UQCRC2-related mitochondrial responses. Collectively, these findings highlight UQCRC2 as a redox-sensitive mitochondrial node linking Complex III dysfunction to cardiometabolic injury and targeted redox-based interventions. Full article

6:2 chlorinated polyfluorinated ether sulfonate (F-53B, also known as 6:2 Cl-PFESA) is a major alternative to perfluorooctane sulfonate (PFOS) and a widespread environmental pollutant with potential public health hazards. However, its nephrotoxic effects and underlying molecular mechanisms remain poorly understood. This study investigated renal injury induced by environmentally relevant concentrations of F-53B and delineated the mechanistic cascade using a mouse model combined with quantitative proteomic and molecular biological approaches. Male C57BL/6 mice were exposed to 0, 4, 40, and 400 μg/L F-53B for 4 weeks. F-53B exposure led to significant renal dysfunction, histopathological damage, elevated renal injury biomarkers, and pronounced oxidative stress in a dose-dependent manner. A proteomic comparison of the 0 μg/L versus 400 μg/L groups identified 276 differentially expressed proteins that were strongly enriched in oxidative phosphorylation, autophagy, and apoptosis pathways, with cytochrome c oxidase subunit 7b (Cox7b) serving as a core downregulated hub molecule. Further validation confirmed that F-53B triggered overt mitochondrial structural damage, impaired respiratory chain complex assembly, aberrant ATP production, and disturbed mitochondrial dynamics. Consequently, excessive autophagy activation and mitochondrial-mediated apoptosis were simultaneously stimulated in renal tissues. Notably, although statistically significant, the alterations induced by F-53B were generally mild in magnitude. Collectively, our findings demonstrate that F-53B induces nephrotoxicity through a sequential pathological cascade. This study provides novel mechanistic insights into F-53B-elicited renal injury and highlights the potential health risks of this emerging per- and polyfluoroalkyl substance (PFAS) alternative. Full article

Background: This study investigated the relationships among mitochondrial energy metabolism, immune function, and gut microbiota in mice under a fatigued state, providing preliminary evidence for future nutrition-related mechanistic and intervention studies. Methods: Mice were adaptively fed for 4 days and then randomly divided into a normal control group (NC) and a fatigue model group (NM). Immune organ indices, serum IgG levels, thigh muscle ATP content, mitochondrial respiratory chain complex I–IV activities, and gut microbiota composition were assessed using enzyme-linked immunosorbent assay (ELISA), microplate assays, and 16S rRNA gene sequencing. Results: Compared with the NC, the NM showed a significantly reduced spleen index, serum IgG levels, mitochondrial respiratory chain complex I, III, and IV activities, along with reduced ATP content. Regarding gut microbiota, mice in the NM exhibited disordered intestinal villus arrangement, inflammatory cell infiltration in the crypts and muscular layers, and markedly reduced intestinal microbial activity as well as protease and sucrase activities. 16S rRNA sequencing revealed fewer ASVs in the NM, with enrichment of Lactobacillaceae, Limosilactobacillus, and Ligilactobacillus, whereas the NC was characterized by Borkfalkiaceae and Borkfalkia. Linear discriminant analysis effect size (LEfSe) analysis identified Lactobacillaceae, Firmicutes_D, and Lactobacillales as characteristic taxa of the NM. Kyoto Encyclopedia of Genes and Genomes (KEGG) prediction indicated that fatigue-associated microbial functions were mainly related to carbohydrate, amino acid, and lipid metabolism. Correlation and RDA analyses further suggested that alterations in gut microbiota structure were closely associated with mitochondrial energy-related indicators and immune-related parameters. Conclusions: Fatigue was associated with alterations in energy metabolism, immune function, and gut microecology in mice. The “gut microbiota–energy metabolism–immunity” framework may represent a potential association-based framework and provides biological information to support future nutrition-related intervention studies. Full article

Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission–fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development. Full article

Physiotherapy is an evidence-based healthcare occupation aiming to collaborate in the diagnosis, prevention and treatment of a myriad of diseases and clinical scenarios throughout all stages of human life. Its development has been accelerated over the last two decades. The scope of physiotherapy is continuously evolvig. However, the accumulated evidence in the context of rare diseases is scarce. Remarkably, the opportunity for improvement and potential benefit for complex diseases with low prevalence is also very high, both as an isolated approach or within multidisciplinary specialized units. Systemic light-chain (AL) amyloidosis is a rare, chronic, complex, heterogeneous, incurable, and challenging disease, which may involve different organs and systems, including the heart, kidney, liver, peripheral nerves, lung, muscle, skin, and others. Heart is the most frequently involved organ leading to failure and arrhythmias. Peripheral neuropathy is a relatively frequent symptom. Renal, respiratory, and hepatic failure may also occur. The aim of this narrative review is summarizing, updating, and critically underlining potential new avenues of development on the role of physiotherapy in systemic light-chain (AL) amyloidosis, compared with its application in multiple myeloma, a closely related but not so rare entity. Full article

Cannabinoids are potential anticancer agents for the add-on treatment of malignant tumors. Here, the effects of the previously less-explored non-psychoactive phytocannabinoids cannabigerol (CBG) and cannabichromene (CBC) on survival, apoptosis, and mitochondrial function were assessed in A549 and H460 lung cancer cells. CBG and CBC triggered concentration-dependent cell death, autophagy, and mitochondrial apoptosis in both cell lines, with apoptosis indicated by Annexin V staining, activation of caspase-8, -9, and -3/7, loss of mitochondrial membrane potential, and elevated cytosolic levels of mitochondrial cytochrome c. CBG also upregulated ATF4, a stress-responsive transcription factor involved in autophagy and apoptotic signaling, and enhanced PARP cleavage. Both cannabinoids increased mitochondrial superoxide formation and reduced the mitochondrial oxygen consumption rate, with CBG additionally decreasing NDUFB8, a subunit of respiratory chain complex I. Pharmacological receptor modulation showed that CBG- and CBC-induced cell death occurred independently of CB₁, CB₂, TRPV1, TRPM8, and PPARγ, whereas CBG-mediated cell death relied on PPARα, which also contributed to its apoptotic effects. In summary, CBG and CBC induce apoptosis and cell death in A549 and H460 cells, with PPARα mediating the effects of CBG, highlighting its potential as a therapeutic target. Full article

Mitochondrial electron transport chain (ETC) dysfunction is a major driver of bioenergetic failure, redox imbalance, and drug toxicity, yet strategies to restore oxidative phosphorylation under ETC blockade remain limited. Redox-active small molecules could, in principle, shuttle electrons from NADH to distal ETC components and oxygen, thereby modulating both respiration and reactive oxygen species (ROS) formation. Here, we show that the enzyme-independent redox cycler phenazine methosulfate (PMS) rewires mitochondrial redox circuits and restores respiration in human glioblastoma cells and cell-free systems under ETC inhibition. At subtoxic concentrations, PMS acutely increased oxygen consumption and mitochondrial superoxide generation via NADH–PMS–O₂ redox cycling, while restoring mitochondrial membrane potential and ATP synthesis under ETC blockade, and shifting metabolism away from glycolytic lactate production. This profile is consistent with a protective redox-bypass role, distinct from the pro-apoptotic effects reported following high-dose, prolonged PMS exposure. The PMS-driven restoration of electron flow, mitochondrial membrane potential, and respiratory ATP synthesis under inhibition of Complex I (rotenone), III (antimycin A and myxothiazol), and/or IV (cyanide) is consistent with direct cytochrome c reduction, as demonstrated herein, and engagement of multiple ETC redox centers, including coenzyme Q₁₀. In metformin-treated cells, PMS reversed suppression of respiration and lactate accumulation, outperforming existing redox-bypass strategies. These findings identify PMS-driven redox cycling as a previously unrecognized chemical redox-bypass mechanism that both regenerates mitochondrial bioenergetics and reshapes ROS production, suggesting a potential approach to counteract drug- and toxin-induced mitochondrial dysfunction and to exploit redox vulnerabilities in cancer. Full article

Mitochondrial dysfunction in colonic smooth muscle cells (SMCs) is closely associated with impaired gut motility in functional constipation (FC), but the underlying molecular mechanisms remain incompletely understood. The mitochondrial unfolded protein response (UPR^mt) is a critical pathway for maintaining mitochondrial proteostasis, and heat shock factor 1 (HSF1) acts as an important upstream regulator of this response. In the present study, we employed a loperamide-induced FC mouse model, combined with single-cell transcriptomic, molecular, and functional analyses to characterize the HSF1-UPR^mt pathway in colonic SMCs and to investigate its role in FC. Single-cell transcriptomic analysis of colon tissue from FC mice revealed marked downregulation of UPR^mt-associated genes in colonic SMCs. Immunofluorescence, Western blotting, and RT-qPCR analyses of colonic tissue confirmed that HSF1 expression was reduced in colonic SMCs, along with the downregulation of the UPR^mt components, including HSP60, mtHSP70, and LONP1. These molecular changes were accompanied by mitochondrial structural damage, seen by transmission electron microscopy, and by functional impairments, including reduced mitochondrial membrane potential, elevated mtROS production, decreased ATP levels, and diminished activities of respiratory chain complexes I–V. AAV9-mediated overexpression of HSF1 reactivated the UPR^mt pathway, improved mitochondrial function, and ameliorated constipation, whereas shRNA-mediated knockdown of HSF1 further suppressed UPR^mt activity and aggravated mitochondrial damage, indicating that HSF1 bidirectionally regulates this pathway. Complementary experiments in primary colonic SMCs confirmed that this regulatory mechanism operates in a cell-autonomous manner, as modulation of HSF1 expression produced corresponding changes in the UPR^mt pathway, in the expression of mitochondrial respiratory chain complex subunits (ATP5A, NDUFA9, COX1, SDHA, UQCRC1), and in ATP production, mirroring the in vivo findings. Collectively, these results demonstrate that HSF1 plays a pivotal role in maintaining mitochondrial homeostasis in colonic SMCs through regulation of the UPR^mt pathway and that HSF1 dysfunction is closely associated with slowed gut motility in FC. These findings offer a new mechanistic perspective on FC and point to the HSF1–UPR^mt axis as a potential therapeutic target. Full article

Complex II deficiency is a rare inherited mitochondrial disorder characterized by structural and functional deficiency of complex II, for which there is currently no definitive drug treatment. Curcumin is a polyphenolic compound with antioxidant, anti-inflammatory, anti-tumor, and anti-aging properties. By constructing a mutant strain of the Saccharomyces cerevisiaeSDH2 gene, we can mimic the functional defects of Complex II caused by human SDHB mutations, and then explore the ameliorative effect of curcumin on Complex II functional defects. Cell viability was assessed using MTT and CFU. Antioxidant capacity was evaluated by measuring DCFH-DA and antioxidant enzyme activity, while the expression levels of respiratory chain-related genes were detected by qRT-PCR. Experimental results demonstrate that curcumin can restore cell growth and viability, scavenge ROS from cells as well as positively regulate mitochondrial function; however, the above results are regulated by the concentration of curcumin. In conclusion, these findings provide experimental support for curcumin as a preliminary intervention for Complex II deficiency and other mitochondrial diseases, further enriching the evidence for the potential application of curcumin in mitochondrial-related diseases. Full article

Methamphetamine (METH)-induced cardiomyocyte injury is the leading cause of mortality beyond acute intoxication. METH abuse often occurs in crowded, poorly ventilated environments, and even moderately high ambient temperatures exacerbate METH-related cardiovascular emergencies. However, the underlying mechanisms by which environmental factors drive the progression of cardiac diseases remain poorly understood. This study modeled the real-world scenario in vivo by exposing mice to METH under normothermic condition (NC, 22 °C) or subthreshold thermal stress (STS, 28 °C, a mild thermal challenge for mice) conditions, and in vitro by using H9c2 cardiomyocytes exposed to METH at 37 °C or 39 °C. STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial ultrastructural damage, and oxidative stress (p < 0.05). Mechanistically, the co-exposure impaired mitochondrial respiratory chain complex I and led to excessive mitochondrial ROS (mtROS) production, activating the pro-apoptotic protein BAX, causing mitochondrial outer membrane (MOM) permeabilization and the cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA-mediated NLRP3 inflammasome activation subsequently executed cardiomyocyte pyroptosis via caspase-1/Gasdermin D (p < 0.05). Crucially, the mitochondria-targeted antioxidant mitoquinone (MitoQ) substantially attenuated the aggravated cardiotoxicity by scavenging the initial mtROS (p < 0.05), thereby preventing the activation of the downstream BAX/mtDNA/NLRP3 axis. These findings provide evidence for a defined signaling basis for this drug-environment interaction and highlight mitochondrial redox modulation as a potential therapeutic strategy for psychostimulant-associated cardiovascular injury. Full article

The global prevalence of pulmonary infections caused by non-tuberculous Mycobacteria (NTM), particularly the Mycobacterium avium complex (MAC), is increasing. Since NTM are ubiquitous in moist environments and resistant to standard disinfectants, this study evaluated the efficacy of chlorous acid water (CAW) against them. CAW demonstrated superior sanitizing effects compared to sodium hypochlorite (NaClO), efficiently inactivating NTM at 100 mg/L free available chlorine even in the presence of organic matter, where 1000 mg/L NaClO failed. Instead, subcellular fractionation and protein analysis revealed that CAW penetrates the cell to induce extensive aggregation of internal functional proteins, leading to the rapid collapse of membrane potential and ATP production. Furthermore, CAW exhibited significantly lower cytotoxicity toward human lung-derived A549 cells than NaClO. These results indicate that CAW inactivates NTM effectively by targeting internal protein stability and the respiratory chain, offering a potent and safer disinfection strategy for clinical and domestic environments. Full article

Background/Objectives: α-Mangostin, a natural product from Garcinia mangostana L, presents very strong antibacterial activity in plant flavonoids against Staphylococcus aureus. Recently, it was reported that the quinone pool is a key target of α-mangostin against Gram-positive bacteria. Here, the detail centering this action mechanism of α-mangostin killing S. aureus was further explored. Methods: The interactions between α-mangostin and type II NADH:quinone oxidoreductase (NDH-2), a key enzyme in the respiratory chain, were explored through the enzyme kinetic experiments, fluorescence analyses, and molecular simulation. Simultaneously, the effect of α-mangostin on membrane potential was also investigated as a possible non-enzymatic mechanism. Results: it was found that α-mangostin mainly competes the menaquinone-binding sites of NDH-2 with menaquinone, and the half-maximal inhibitory concentration (IC₅₀) of α-mangostin on NDH-2 is 4.95 μM. Fluorescence analyses indicated that α-mangostin can spontaneously bind to NDH-2 to form an α-mangostin–NDH-2 complex. Subsequently, molecular simulation further showed that α-mangostin can dock to the menaquinone-binding sites of NDH-2. In addition, non-enzymatic mechanism showed that α-mangostin can cause membrane potential depolarization and disrupt the proton motive force balance, thereby promoting the cell-membrane destruction of S. aureus. Conclusions: α-Mangostin can mainly interact with the amino acid residues at the menaquinone-binding pocket of NDH-2 to block the electron transfer at the quinone pool in the respiratory chain of S. aureus, which will hinder the energy supply and act synergistically with cell membrane damage, ultimately leading to the death of S. aureus. Simultaneously, it once again proves that the quinone pool is a key target of plant flavonoids against Gram-positive bacteria. Full article

During fermentation in stirred-tank bioreactors (STBR), filamentous fungi are frequently exposed to hypoxic conditions. However, their responses, especially short-term ones (≤6 h), remain unclear. In this study, we performed a short-term multi-omics profiling in an Aspergillus oryzae hyphal dispersion mutant (AGΔ-GAGΔ) during a controlled transition to hypoxia (a decrease in dissolved oxygen (DO) from 10% to ≤1%) in a 4 L STBR. In transcriptome analysis, the genes encoding mitochondrial respiratory chain Complexes I–III were transiently downregulated at 1 h from DO depletion and were then upregulated, whereas those of Complex IV were upregulated immediately at the onset of hypoxia. In relation to this respiratory remodeling, we also observed an immediate induction of an alternative oxidase (AOX) gene. However, our metabolome data showed no significant change in the ATP level. This result could be explained by the upregulation of the glycolytic genes in hypoxic cultures. Fluorescence imaging revealed a transient increase in intracellular reactive oxygen species (ROS) in hypoxia, and metabolomics data revealed a decrease in the reduced glutathione/oxidized glutathione ratio in hypoxic cultures. Deletion of the AOX gene prolonged the ROS increase. Together, these data indicate that early hypoxia triggers a transient increase in oxidative stress, mitigated by antioxidant systems and mitochondrial respiratory rebalancing including an AOX-mediated bypass. Full article

Brucellosis, acting as a typical chronic zoonotic disease, is caused by the invasion of Brucella into the human body. Outer membrane protein 25 (Omp25), specifically localized on the Brucella membrane, is the main virulence factor of Brucella and participates in multiple links of the damage process. Omp25c, a porin protein of Brucella, is a paralog of Omp25 with high sequence identity. NADH dehydrogenase [ubiquinone] complex I assembly factor 2 (Ndufaf2) has a key function in cell energy metabolism, particularly in the formation and activity of the mitochondrial respiratory chain. Loss of Ndufaf2 results in oxidative stress and mitochondrial DNA (mtDNA) deletion. However, the functional relationship between Omp25c and Ndufaf2, the underlying mechanism of the proteins, remains unclear. In this work, we purified the Omp25c and Ndufaf2proteins. Our data revealed that Omp25c directly interacts with Ndufaf2, as determined using Biacore analysis. In addition, assays revealed that Ompa2c reshapes the host cell’s redox environment by decreasing the oxidized nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD⁺/NADH) ratioand adenosine triphosphate (ATP) production, whereas Ndufaf2 exerts an opposing regulatory effect; Co-expression results further revealed an antagonistic relationship between the two during metabolic processes. These findings provide a new perspective for elucidating the mechanisms of mitochondrial functional regulation in Brucella–host interactions and lay the theoretical and experimental foundation for drug development targeting metabolic interventions to eliminate intracellular pathogens. Full article

The emerging problem that microplastics pose to our society is reflected in the exponential growth in investigations devoted to uncovering their toxicological potential in humans. However, these studies present several limitations, one of the most significant being the use of microplastics that do not represent their environmental counterparts. In this study, we evaluated the impact of two types of polyethylene microplastics (27–32 µm)—non-fluorescent and fluorescent—on the liver and intestine, targeting mitochondria. FVB/n mice were subjected to a subacute exposure to two concentrations representative of human exposure (0.002% (w/w) and 0.006% (w/w)). Both types of microplastics impaired mitochondrial respiration through disruption of NADH-linked pathways, with more pronounced effects at the highest concentration of fluorescent MPs. Electron transport chain complexes, particularly CIII and CIV, were affected, partially explaining the observed alterations in mitochondrial respiratory capacity. An increased SOD and GPx activity supported the link between mitochondrial dysfunction and increased reactive oxygen species overproduction under MPs exposure. Hepatic mitochondrial lipid remodelling was detected following exposure to fluorescent microplastics, while intestinal epithelial cells displayed impaired mitochondrial activity together with compromised cellular integrity, indicative of stress response. In parallel, shifts in gut composition suggest that PE MPs may contribute to intestinal barrier dysfunction. Overall, fluorescent MPs induced more severe mitochondrial and biochemical disturbances in both the liver and the intestine than their non-fluorescent counterparts. Our findings highlight mitochondria as central targets for microplastic-induced toxicity and underscore the need for improved MPs models in toxicological research. Full article