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Effects of PM2.5 on oxidative stress and mitochondrial damage in vitro. (A) After different dose of PM2.5 exposed for 24 h in Beas-2b cells, total ROS were measured in Beas-2b cells. (B) Western blot analysis showed the expression levels of NOX4 and Nrf2 in dose-depend manner, (C) time-depend manner and the relative density. (E-G) After treated with different concentration of PM2.5 for 24 h in Beas-2b cells, the expression levels of oxidants (MDA) and antioxidants (GSH/GSSG and SOD) were determined. (H) The mitochondrial ROS in different concentration of PM2.5 were determined by MitoSOX staining. (I) Mitochondrial membrane potential were measured by TMRM staining in different concentration of PM2.5 for 24 h. (J) Western blot analysis showed the expression levels of Drp1, SIRT3, Cyto-c and AIF in different concentration of PM2.5 (50,
Source publication
The increasing abundance of fine particulate matter (PM2.5) in the environment has increased susceptibility to acute exacerbation of COPD (AECOPD). During PM2.5 exposure, excessive reactive oxygen species (ROS) production triggers a redox imbalance, which contributes to damage to organelles and disruption of homeostasis. At present, there are limit...
Contexts in source publication
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... stress plays a major role in PM2.5-mediated lung injury. To analyze the level of oxidative stress in Beas-2b cells treated with PM2.5, the level of ROS generation, the ratio of NOX4/Nrf2 expression, and the expression levels of GSH/GSSG, SOD and MDA were examined. As shown in Fig. 1A, PM2.5 significantly increased the levels of ROS in a dose-dependent manner, leading to redox imbalance. This imbalance was associated with deficient activation of Nrf2, which is a master regulator of antioxidant genes, and sustained activation of NOX4 in a dose-and time-dependent manner ( Fig. 1B-D). Moreover, the levels of oxidant ...
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... GSH/GSSG, SOD and MDA were examined. As shown in Fig. 1A, PM2.5 significantly increased the levels of ROS in a dose-dependent manner, leading to redox imbalance. This imbalance was associated with deficient activation of Nrf2, which is a master regulator of antioxidant genes, and sustained activation of NOX4 in a dose-and time-dependent manner ( Fig. 1B-D). Moreover, the levels of oxidant and antioxidant enzymes, including GSH/GSSG, SOD and MDA, were obviously changed in high-dose PM2.5 (400 μg/ml) group ( Fig. 1E-G). These data indicate that PM2.5 triggers oxidative stress in Beas-2b cells via a NOX4/Nrf2 redox imbalance in a dose-dependent manner. To examine the mitochondrial damage ...
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... imbalance was associated with deficient activation of Nrf2, which is a master regulator of antioxidant genes, and sustained activation of NOX4 in a dose-and time-dependent manner ( Fig. 1B-D). Moreover, the levels of oxidant and antioxidant enzymes, including GSH/GSSG, SOD and MDA, were obviously changed in high-dose PM2.5 (400 μg/ml) group ( Fig. 1E-G). These data indicate that PM2.5 triggers oxidative stress in Beas-2b cells via a NOX4/Nrf2 redox imbalance in a dose-dependent manner. To examine the mitochondrial damage induced by PM2.5, the mito-ROS levels, mitochondrial membrane potential and mitochondrial function-related protein levels were measured. Compared with the control ...
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... the mitochondrial damage induced by PM2.5, the mito-ROS levels, mitochondrial membrane potential and mitochondrial function-related protein levels were measured. Compared with the control and low-dose PM2.5 groups, the high-dose PM2.5 (400 μg/ml) group exhibited significant increases in mito-ROS generation and decreased in membrane potential ( Fig. 1H and I). Then, we measured the protein expression of cyto-c, AIF and DRP1, which play key roles in mitochondrial fission. The results showed that the expression levels of DRP1, cyto-c and AIF were significantly increased in the PM2.5 (400 μg/ ml) group compared with the control and low-dose PM2.5 groups. SIRT3, which is a protein that ...
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... which play key roles in mitochondrial fission. The results showed that the expression levels of DRP1, cyto-c and AIF were significantly increased in the PM2.5 (400 μg/ ml) group compared with the control and low-dose PM2.5 groups. SIRT3, which is a protein that regulates mitochondrial metabolism, was decreased by PM2.5 in a dose-dependent manner (Fig. 1J). The cytotoxicity and apoptosis were significantly increased in the PM2.5 (400 μg/ml) group compared with the control and low-dose PM2.5 groups ( Supplementary Fig. 1). These data suggest that PM2.5 triggers oxidative stress and mitochondrial damage in a dose-dependent manner in Beas-2b ...
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... which is a protein that regulates mitochondrial metabolism, was decreased by PM2.5 in a dose-dependent manner (Fig. 1J). The cytotoxicity and apoptosis were significantly increased in the PM2.5 (400 μg/ml) group compared with the control and low-dose PM2.5 groups ( Supplementary Fig. 1). These data suggest that PM2.5 triggers oxidative stress and mitochondrial damage in a dose-dependent manner in Beas-2b cells. ...
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... on PM2.5-induced mitophagy and mitochondrial damage were investigated in CS-exposed mice. The mice in the treatment group showed more significant activation of the key mitophagy and mitochondrial-related proteins mTOR, p62, TOM20, TIM23 and SIRT3 and inhibition of LC3-II, ATG3, PINK1, Parkin, Drp1, cyto-c and AIF than the AECOPD model mice (Fig. 10A-F). Both of these agents can inhibit the production of ROS and autophagy. The results showed that inhibition of ROS production improved mitophagy and mitochondrial damage, as shown by a decreased number of TUNEL-positive cells (Fig. 10G), and the damage to the mitochondrial structure, mitochondrial vacuolation and mitophagy were decreased ...
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... TIM23 and SIRT3 and inhibition of LC3-II, ATG3, PINK1, Parkin, Drp1, cyto-c and AIF than the AECOPD model mice (Fig. 10A-F). Both of these agents can inhibit the production of ROS and autophagy. The results showed that inhibition of ROS production improved mitophagy and mitochondrial damage, as shown by a decreased number of TUNEL-positive cells (Fig. 10G), and the damage to the mitochondrial structure, mitochondrial vacuolation and mitophagy were decreased according to TEM (Fig. 10H and I). These results suggested that inhibiting ROS production to reestablish the NOX4/Nrf2 redox balance can ameliorate PM2.5-induced mitochondrial damage and mitophagy in CS-exposed ...
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... of these agents can inhibit the production of ROS and autophagy. The results showed that inhibition of ROS production improved mitophagy and mitochondrial damage, as shown by a decreased number of TUNEL-positive cells (Fig. 10G), and the damage to the mitochondrial structure, mitochondrial vacuolation and mitophagy were decreased according to TEM (Fig. 10H and I). These results suggested that inhibiting ROS production to reestablish the NOX4/Nrf2 redox balance can ameliorate PM2.5-induced mitochondrial damage and mitophagy in CS-exposed ...
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Background
The recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains a major clinical problem. Cells that survive the sublethal heat stress that is induced by incomplete RFA are the main source of HCC relapse. Heat stress has long been reported to increase intracellular reactive oxygen species (ROS) generation. Al...
Citations
... Therefore, it makes sense to anticipate that damaged mitochondria will be removed by the process of mitophagy, which is the activation of a quality control mechanism. To keep the mitochondria intact, mitophagy is necessary because it maintains the proper ratio of healthy to damage mitochondria, hence regulating the quality of mitochondria [44]. A prior study demonstrated that mitophagy is intricately associated with the generation of ROS [45]. ...
Microplastics (MPs) are widespread environmental pollutants that can enter the human body through the food chain, potentially leading to lung damage. However, the underlying mechanisms responsible for this damage remain unclear. Ducks, a commonly consumed poultry species in China, are particularly susceptible to MPs exposure due to their farming environment. In this study, Shaoxing ducklings were administered two distinct concentrations of polystyrene microplastics (PS-MPs) (1 mg/L and 100 mg/L) via oral route, alongside a control group, over a period of four weeks to establish an in vivo model for evaluating the effects of microplastic exposure in ducks. Simultaneously, rat type II alveolar epithelial (RLE-6TN) cells were exposed to different concentrations of PS-MPs (0, 10, 100, and 500 µg/mL) for 48 h, thereby constructing an in vitro exposure model. Our results showed that PS-MPs caused pathological damage, inflammatory cell infiltration, and activation of the LPS/TLR4 inflammatory pathway in the lung. Further analysis revealed that PS-MPs disrupted the tricarboxylic acid (TCA) cycle and inhibited oxidative phosphorylation. Mechanistic investigation demonstrated that PS-MPs induced mitochondrial dysfunction and consequent excessive mitophagy. This study investigates the mechanisms by which PS-MPs contribute to mitochondrial dysfunction and mitophagy, potentially exacerbating lung inflammation, offering valuable insights for mitigating the toxic effects of PS-MPs on human and animal health.
Graphical Abstract
... PM 2.5 exposure suppresses the expression of superoxide dismutase 2 (SOD-2) in skeletal muscle (126). The downregulation of antioxidant enzyme expression disrupts the redox balance in the body (128), leading to excessive accumulation of ROS within mitochondria. This persistent oxidative stress response reduces the expression of mitochondrial DNA (mtDNA) (42). ...
This study aims to explore the multifaceted impacts and mechanisms of fine particulate matter (PM2.5) exposure on skeletal muscle mitochondria. Evidence suggests that PM2.5 can penetrate the respiratory barrier and enter the circulatory system, spreading throughout the body and causing significant damage to the morphology, quantity, and function of skeletal muscle mitochondria. This is manifested by a decline in oxidative phosphorylation efficiency and mitochondrial dysfunction. Meanwhile, PM2.5 exposure induces excessive production of reactive oxygen species, triggering oxidative stress responses that impair mitochondrial dynamic regulation. This further disrupts the balance of glucose and lipid metabolism in skeletal muscle, exacerbating the development of metabolic diseases. The review underscores the systemic effects on skeletal muscle following mitochondrial dysfunction after PM2.5 exposure and the preventive and treatment potential of exercise.
... This study provides evidence-based phased implementation strategies for provinces facing challenges in achieving national targets, supporting the implementation of regionally adaptable interim standards during transitional phases. Some mechanism studies may explain the results: According to Fan et al. (26), PM2.5 exposure enhanced mitophagy via triphosphopyridine nucleotide oxidase 4 (NOX4)/ transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) redox imbalance, further increasing susceptibility to acute exacerbation of COPD (AECOPD). Research by Guo et al. (27) showed PM2.5 exposure up-regulated the expression of methyltransferase-like protein 16 (METTL16), subsequently altered N6-methyladenosine (m6A) modification, and finally microvascular injury in COPD. ...
Background
Air pollution caused by ambient fine particulate matter (≤ 2.5 μm) adversely affects human health. Previous studies have shown that PM2.5 exposure increases the risk of lung diseases. However, the relationship between long-term PM2.5 exposure and new-onset lung diseases among middle-aged and older adults in China is still unclear.
Methods
We conducted a retrospective cohort study through the China Health and Retirement Longitudinal Study (CHARLS) and Science Data Bank (ScienceDB). The logistic regression model and restricted cubic spline (RCS) were used to explore the relationship between long-term PM2.5 exposure and new-onset lung diseases. To further increase the robustness of the results, we performed sensitivity and subgroup analyses.
Results
A total of 10,707 patients were included in this study. The 10,707 patients were divided into two groups: without new-onset lung diseases (n = 9,019) and with new-onset lung diseases (n = 1,688). The results of multivariate analysis showed that per 1 ug/m³ increase in annual PM2.5 concentration, the risk of new lung diseases increased by 0.3%. The results of the RCS showed that PM2.5 exposure increased the risk of new-onset lung diseases more significantly when the annual PM2.5 concentration was greater than 48.5 ug/m³. Sensitivity analysis and subgroup analysis also confirmed the reliability of the results.
Conclusion
PM2.5 exposure increases the risk of new-onset lung diseases among middle-aged and old adults in China, especially when the concentration of PM2.5 > 48.5 ug/m³. Our study established an empirical foundation for refining PM2.5 emission regulations, developing age-stratified screening protocols for incident pulmonary diseases, and advancing mechanistic investigations into PM2.5-induced lung pathology.
... SFTPA1 promotes increased necroptosis of type II alveolar epithelial cells through the IRE1α-JNK axis and the progression of idiopathic pulmonary fibrosis (IPF) [25]. Although relevant studies have shown that PM 2.5 exposure can cause a variety of cell death modes, such as ferroptosis [26], autophagy [27], and pyroptosis [28], there are few studies on the mechanisms related to PM 2.5 exposure and necroptosis. ...
... Initially, the PM 2.5 exposure model of the AD cell line was established, and two neuronal cell lines, HT22 and SH-SY5Y, were chosen. Utilizing the CCK8 assay, it was observed that the survival rate of both neuron cell types diminished progressively with escalating concentrations of Aβ [25][26][27][28][29][30][31][32][33][34][35] exposure. Considering the cellular damage inflicted by co-exposure, 15 µM and 20 µM were selected as therapeutic concentrations for HT22 and SH-SY5Y cells, respectively. ...
... Considering the cellular damage inflicted by co-exposure, 15 µM and 20 µM were selected as therapeutic concentrations for HT22 and SH-SY5Y cells, respectively. Subsequently, it was determined that the IC50 values for HT22 and SH-SY5Y cells under PM 2.5 exposure were 174.1 and 233.1 µg/mL, respectively, following co-exposure to Aβ [25][26][27][28][29][30][31][32][33][34][35] and PM 2.5 ( Figure 1A,B). In this study, to investigate the effects of PM 2.5 exposure on the occurrence and progression of necroptosis in AD neurons, we detected necroptosisrelated markers, such as RIPK1, p-RIPK1, MLKL, and p-MLKL, in HT22 and SH-SY5Y cells. ...
Recent epidemiological studies have indicated that exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less in the ambient air (PM2.5) is significantly associated with an elevated risk of developing Alzheimer’s disease (AD) and its progression. Scorpion venom heat-resistant synthetic peptide (SVHRSP) exhibits anti-inflammatory and neuroprotective properties. However, the exact ways in which SVHRSP mitigates the progression of AD induced by PM2.5 are still unknown. Long non-coding RNA (lncRNA) plays a crucial role in various biological processes. Necroptosis, a form of programmed cell death, has garnered considerable attention in recent years. This study aims to investigate whether Lnc Gm16410 and neuronal necroptosis are involved in PM2.5-exacerbated AD progression and the mechanisms of SVHRSP in alleviating this process. Through the establishment of a PM2.5 exposure model in AD mice and an in vitro model, it was found that PM2.5 exposure could promote necroptosis and the down-regulation of Lnc Gm16410, thereby promoting the progression of AD. Behavioral tests showed that SVHRSP alleviated cognitive impairment in PM2.5-induced AD mice. WB, qRT-PCR, and other molecular biological assays indicate that Lnc Gm16410 regulates neuronal necroptosis under PM2.5 exposure via the p38 MAPK pathway. SVHRSP is a potential regulator of AD progression by regulating Lnc Gm16410 to alleviate PM2.5 exposure-induced necroptosis. These findings offer new insights into the mechanism through which PM2.5 exposure accelerates the progression of AD, examined from the perspective of LncRNA. Furthermore, we offer new targets for the treatment and prevention of AD following PM2.5 exposure by investigating the mechanism of action of SVHRSP in alleviating AD.
... (57). African-American populations live in areas with higher mean annual PM2.5 concentrations than white people (57,58), and PM2.5 is able to penetrate deep lung tissues, triggering oxidative stress and inflammatory responses that lead to mitochondrial dysfunction and lung injury (59), contributing to acute exacerbations of COPD (60). The anti-inflammatory capacity of lc9 metabolic indicators (e.g., BMI, glycemic control) may be weakened. ...
Background
Chronic Obstructive Pulmonary Disease (COPD) is a major global health concern, with lifestyle factors playing a crucial role in its prevention. This study aims to explore the relationship between Life’s Crucial 9 (lc9) scores and COPD odds, and to assess the mediating potential of lean body mass (LBM) in this association.
Methods
This study used cross-sectional study to assess the association between lc9 score and COPD using data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020. Weighted multivariate regression analyses were performed to examine lc9 score on the odds of COPD after adjusting for confounders. The models were adjusted for age, gender, race/ethnicity, Marital status, education level, Family income-to-poverty ratio, LBM and Alcohol consumption status. The discrimination ability of lc9 on COPD odds was evaluated using (ROC) curve. Mediation analysis was used to investigate the mediating potential of LBM between lc9 and COPD odds. Subgroup analyses and interaction assessments were also performed.
Results
In Model 2, the results showed that for every 10-point change in the lc9 score, the odds of developing COPD decreased. The OR (95% CI) in the Moderate and High groups were OR = 0.37; 95% CI: 0.23, 0.59 and OR = 0.16; 95% CI: 0.09, 0.27 (P for trend < 0.001), respectively. In addition, the results for quartile subgroups were Q3, OR = 0.58; 95% CI: 0.42, 0.81), Q4, OR = 0.24; 95% CI: 0.16, 0.36) and P for trend < 0.001. This relationship was consistent across the total population, subgroup analyses, and sensitivity analyses. There was a nonlinear relationship between lc9 score and odds of COPD (P for Nonlinear = 0.022). The lc9 reduced the odds of COPD by increasing LBM. The lc9 is an suggestive predictor of COPD odds association.
Conclusions
Higher LC9 scores, particularly when accompanied by increased LBM levels, showed significant associations with reduced COPD risk in cross-sectional analyses.
... Various mechanisms, such as DNA damage, decline in membrane potential, and overexpression of ROS, can lead to mitochondrial damage induced by air pollutants. This can cause disruptions in energy metabolism and cell apoptosis [131][132][133][134]. Low exposure levels to PM2.5 (200 µg/mL) increase ROS production, exacerbate imbalances in NOX4/Nrf2 Reduction-Oxidation (Redox), reduce mitochondrial membrane potential, and ultimately intensify oxidative stress as well as mitochondrial damage [135]. PM2.5 exposure elevates ROS levels, apoptosis, and the expression of apoptosis-related proteins within mouse brain tissue, indicating that mitochondrial dysfunction contributes to the neurotoxicity of air pollutants [136]. ...
Air pollution exposure has become an international health issue that poses many risks to life and health. The bidirectional regulatory network, known as the oral–gut–brain axis connects the oral cavity, intestine, and central nervous system, as well as its influence on health outcomes from exposure to air pollution is receiving increased attention. This article systematically details the epidemiological evidence linking air pollutants to diseases affecting the oral, respiratory, intestinal, and nervous systems, while also explaining the route of air pollutants via the oral–gut–brain axis. The oral–gut–brain axis anomalies resulting from air pollution and their underlying molecular processes are also covered. The study provides a fresh viewpoint on how exposure to air pollution affects health and investigates cutting-edge preventative and therapeutic techniques.
... For instance, NOX4 enhances ferroptosis in astrocytes by impairing mitochondrial metabolism in Alzheimer's disease 8 . Reestablishing the NOX4 redox balance via NOX4 blockade or mitochondria-specific ROS inhibitor treatment ameliorated the disturbance of mitophagy and attenuated susceptibility to acute exacerbation of chronic obstructive pulmonary disease 9 . Our previous study revealed that genetic or pharmacological inhibition of NOX4 effectively protects against sepsis-induced AKI by suppressing mitochondrial fission and apoptosis 10 . ...
Acute kidney injury (AKI) is a worldwide clinical burden associated with high morbidity and mortality. Remote ischemic preconditioning (rIPC), a brief nonlethal ischemia and reperfusion (IR) in remote tissues or limbs, has been used in an attempt to protect against AKI, but its underlying signaling pathways has not been elucidated. In the present study, rIPC protected kidney function and pathological injury and mitigated NADPH oxidase 4 (NOX4) upregulation in different AKI models (cisplatin, LPS and IRI). Furthermore, rIPC significantly attenuated mitochondrial dysfunction and ameliorated tubular epithelial ferroptosis during AKI. Mechanistically, in wild-type AKI mice and TCMK-1 cells, rIPC effectively decreased kidney ROS production, preserved mitochondrial dynamics and mitophagy, and ameliorated tubular epithelial ferroptosis. Notably, these protective effects of rIPC were further enhanced by NOX4 knockout or silencing and mitigated by NOX4 overexpression. Our study showed that rIPC may attenuate mitochondrial dysfunction and ferroptosis in tubular epithelial cells in AKI by inhibiting NOX4-ROS signaling. NOX4 might be used as a biomarker for monitoring the biological effects of rIPC to optimize the rIPC protocol and facilitate future translational studies.
... The optical density of the CSE was determined, and the extract was used within 1 h. 24 Cell Viability RAW264.7 cells (1 × 104 /well) were stimulated with various levels of CSE (0, 0.05%, 0.1%, 0.15%, 0.2%, 0.4%) for 12 or 24 h. After incubation, 10% CCK8 solution (Dojindo, Japan) was added, and the absorbance of each well was assessed at 450 nm utilizing a microplate reader (BioTek Gen5, BioTek, Shoreline, WA, USA). ...
Objective
Skeletal muscle atrophy is a major comorbidity associated with chronic obstructive pulmonary disease caused by exposure to cigarette smoke (CS). CS-activated macrophages and pyroptosis play an important role in skeletal muscle atrophy, but its specific molecular mechanism remains unclear. This study investigated the role and mechanisms of pyroptosis and activated macrophages in CS-induced skeletal muscle atrophy.
Methods
In the in vivo model, mice were exposed to either CS or air for 24 weeks, and in the in vitro model, C2C12 murine skeletal muscle cells were co-cultured with macrophages in Transwell chambers. Western blotting, real-time PCR, ELISA, and other methods were used to detect pyroptosis-related markers to investigate the mechanism of CSE-activated macrophages on skeletal muscle atrophy and pyroptosis.
Results
In vivo, CS-induced atrophy of the mouse gastrocnemius muscle was accompanied by increased expression of pyroptosis-related markers, including NLRP3 inflammasome, cleaved Caspase-1, the GSDMD N-terminal domain, and interleukin (IL)-18. In vitro, CS extract (CSE)-activated macrophages mediates pyroptosis of skeletal muscle cells and induces myotube atrophy. Further studies demonstrated that macrophage-derived TNF-α is the initiating factor of skeletal muscle pyroptosis, and this process appears to be mediated through TNF-α activating the TNFR1/NLRP3/caspase-1/GSDMD signaling pathway.
Conclusion
TNF-α released by CSE-activated macrophages can promote skeletal muscle pyroptosis by activating the TNFR1/NLRP3/Caspase-1/GSDMD signaling pathway, which likely contributes to skeletal muscle atrophy. These findings provide more insight into the mechanisms underlying skeletal muscle atrophy in COPD.
... mtROS, a byproduct of the mitochondrial respiratory chain, normally plays a significant role in cellular signaling and homeostasis. However, in COPD, increased oxidative stress leads to excessive mtROS production, inducing oxidative stress, abnormal mitophagy, and mitochondrial dysfunction (Fan et al., 2023). mtDNA is the genetic material in mitochondria, responsible for encoding proteins related to energy production and other crucial mitochondrial functions. ...
... A study by Fan showed that in a COPD cell model, high-dose PM2.5 was more likely to trigger oxidative stress and mitophagy in BEAS-2B cells compared with low doses. Notably, under the combined effect of PM2.5-CSE, Parkin and PINK1expression substantially increased,and the application of NADPH Oxidase 4(NOX4) siRNA effectively modulated NOX4/ Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-mediated redox reactions, suppressed ROS generation, and alleviated excessive mitophagy (Fan et al., 2023). Mice exposed to PM2.5-CS exhibited more substantial airway inflammation and mucus hypersecretion compared with those of CS only mice. ...
... Mice exposed to PM2.5-CS exhibited more substantial airway inflammation and mucus hypersecretion compared with those of CS only mice. Additionally, NOX4/Nrf2-mediated redox imbalance and cell apoptosis were considerably exacerbated; however, after treatment with the mitochondrial-targeted antioxidant, MitoTEMPO, the NOX4/Nrf2-mediated redox imbalance was notably improved, with suppressed ROS production and downregulated expression of PINK1 and Parkin (Fan et al., 2023). ...
Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.
... Cells were fixed using an electron microscope fixative (G1102, Servicebio, China) following established protocols. TEM was employed to visualize mitophagy as previously described [ 50 ]. ...
Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor of the urinary system. While tyrosine kinase inhibitors (TKIs) are currently the first-line treatments for advanced/metastatic ccRCC, patients often develop resistance after TKI therapy. Lipid metabolic reprogramming, a hallmark of tumor progression, contributes to acquired drug resistance in various malignant tumors. Mitophagy, a process that maintains mitochondrial homeostasis, aids tumor cells in adapting to microenvironmental changes and consequently developing drug resistance. Solute carrier family 27 member 3 (SLC27A3), highly expressed in lipid-rich tumors like ccRCC, has been associated with poor prognosis. However, the impact of SLC27A3 and the transcription factor complex containing STAT2 on lipid metabolic reprogramming, mitophagy in ccRCC, and their role in TKI resistance remain unexplored. Methods: 786-O to pazopanib resistance was induced by gradient increase of concentration, and the genes related to lipid metabolism were screened by RNA sequencing. Bioinformatics was used to analyze the differential expression of SLC27A3 and its effect on patient prognosis, and to predict the activated pathway in pazopanib-resistant cells. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-coenzyme A (CoA) and lipid metabolomics were performed to screen potential metabolites of SLC27A3. The differential expression of SLC27A3 was detected in clinical samples. The differential expression of SLC27A3 and its effect on drug resistance of ccRCC tumor were detected in vitro and in vivo. Mitophagy was detected by electron microscopy, Mtphagy probe, and Western blot. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were detected by JC-1 and DCF probes. The binding site of the transcription factor complex to the SLC27A3 promoter was detected by dual-luciferase reporter gene assay. Results: SLC27A3, highly expressed in lipid-rich tumors such as ccRCC and glioblastoma, predicts poor prognosis. SLC27A3 expression level also increased in pazopanib-resistant 786-O cells (786-O-PR) with more LD accumulation compared to parental cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Knockdown of SLC27A3 markedly suppressed LD accumulation and mitophagy, and overcame pazopanib resistance in vitro and in vivo. Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation accompanied by ROS production and synthesis of lipid. Overproduced acyl-CoA oxidation in mitochondria resulted in MMP decrease and amounts of ROS production, subsequently triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation and cell death, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation in mitochondria by consuming CPT1A, forcing synthesis of triglycerides and cholesterol esters stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, we found that STAT2 expression was positively correlated to SLC27A3. Transcriptional factor complex containing STAT2 could bind to the promoter of SLC27A3 mRNA to promote SLC27A3 transcription proved by dual-luciferase reporter assay, which also regulated LD metabolism and activated mitophagy during pazopanib resistance. Conclusion: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for β-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid β-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.
