Mitochondrial Function Damage Research Articles

Different amyloid β42 preparations induce different cell death pathways in the model of SH-SY5Y neuroblastoma cells

Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer’s disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NH4OH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH4OH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH4OH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.Graphical

Discovery of Novel Cyclobutyl Oxime Ester Derivatives Containing an α,β-Unsaturated Carbonyl Moiety as Potential Mitochondrial Toxins.

As part of continuous work to explore novel and efficient fungicides originating from natural products, a series of cyclobutyl oxime ester derivatives containing an α,β-unsaturated carbonyl moiety were designed and synthesized. In line with the primary evaluation of the inhibitory effect on common pathogenic fungi causing crop failure, a systematic study on the antifungal activity of target compounds against Rhizoctonia solani was carried out. Most target compounds exhibited satisfactory antifungal activity, and 10 of them were superior to the positive control trifloxystrobin. The most notable median effective concentration (EC50) of compound 6b was 1.70 μg/mL, which was considerable for an intensive study. The control efficacy of compound 6b on potted rice against R. solani was superior to trifloxystrobin at identical concentration. The mycelial morphology and cell membrane permeability of the treated fungi were disrupted, and the meaningful enzyme activities of SDH and POD were also restrained. The reactive oxygen species, nuclear morphology, and mitochondrial membrane potential of the treated hypha reflected an apparent difference compared with the normal morphology, which represented mitochondrial function damage. In addition, chemical features essential for the activity and docking mode within the compound and cytochrome bc1 complex were accessed by computer-aided technology. This study provided insights into the development of new green and efficient fungicides targeting the mitochondria.

Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway

BackgroundWith the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PurposeThe objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. MethodsAn in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. ResultsMice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. ConclusionHAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.

Synthesis, structure–activity relationship and biological evaluation of indole derivatives as anti-Candida albicans agents

In this work, we synthesized a series of indole derivatives to cope with the current increasing fungal infections caused by drug-resistant Candida albicans. All compounds were evaluated for antifungal activities against Candida albicans in vitro, and the structure–activity relationships (SARs) were analyzed. The results indicated that indole derivatives used either alone or in combination with fluconazole showed good activities against fluconazole-resistant Candida albicans. Further mechanisms studies demonstrated that compound 1 could inhibit yeast-to-hypha transition and biofilm formation of Candida albicans, increase the activity of the efflux pump, the damage of mitochondrial function, and the decrease of intracellular ATP content. In vivo studies, further proved the anti-Candida albicans activity of compound 1 by histological observation. Therefore, compound 1 could be considered as a novel antifungal agent.

Identification of 18β-glycyrrhetinic acid as an AGT inhibitor against LPS-induced myocardial dysfunction via high throughput screening

Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb‐derived natural compounds were found inhibiting AGT. 18β-glycyrrhetinic acid (18βGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18βGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18βGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18βGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18βGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.

BTF3L4 Overexpression Mediates APAP-induced Liver Injury in Mouse and Cellular Models.

Acetaminophen (APAP)-induced liver injury (AILI) has an increasing incidence worldwide. However, the mechanisms contributing to such liver injury are largely unknown and no targeted therapy is currently available. The study aimed to investigate the effect of BTF3L4 overexpression on apoptosis and inflammation regulation in vitro and in vivo. We performed a proteomic analysis of the AILI model and found basic transcription factor 3 like 4 (BTF3L4) was the only outlier transcription factor overexpressed in the AILI model in mice. BTF3L4 overexpression increased the degree of liver injury in the AILI model. BTF3L4 exerts its pathogenic effect by inducing an inflammatory response and damaging mitochondrial function. Increased BTF3L4 expression increases the degree of apoptosis, reactive oxygen species generation, and oxidative stress, which induces cell death and liver injury. The damage of mitochondrial function by BTF3L4 triggers a cascade of events, including reactive oxygen species accumulation and oxidative stress. According to the available AILI data, BTF3L4 expression is positively associated with inflammation and may be a potential biomarker of AILI. Our results suggest that BTF3L4 is a pathogenic factor in AILI and may be a potential diagnostic maker for AILI.

Mitochondrial damage-associated molecular patterns: A new insight into metabolic inflammationin type 2 diabetes mellitus.

The pathogenesis of diabetes is accompanied by increased levels of inflammatory factors, also known as "metabolic inflammation", which runs through the whole process of the occurrence and development of the disease. Mitochondria, as the key site of glucose and lipid metabolism, is often accompanied by mitochondrial function damage in type 2 diabetes mellitus (T2DM). Damaged mitochondria release pro-inflammatory factors through damage-related molecular patterns that activate inflammation pathways and reactions to oxidative stress, further aggravate metabolic disorders, and form a vicious circle. Currently, the pathogenesis of diabetes is still unclear, and clinical treatment focuses primarily on symptomatic intervention of the internal environment of disorders of glucose and lipid metabolism with limited clinical efficacy. The proinflammatory effect of mitochondrial damage-associated molecular pattern (mtDAMP) in T2DM provides a new research direction for exploring the pathogenesis and intervention targets of T2DM. Therefore, this review covers the most recent findings on the molecular mechanism and related signalling cascades of inflammation caused by mtDAMP in T2DM and discusses its pathogenic role of it in the pathological process of T2DM to search potential intervention targets.

Integrative transcriptomic and metabolomic analysis reveals the effects of a sudden drop in salinity on osmoregulation, metabolism, anti-oxidation, and immunity in Eriocheir sinensis megalopa and juvenile stages

Eriocheir sinensis has a special habit of migrating from marine to freshwater during its larval developmental stage. Salinity is an important environmental factor affecting the survival rate and growth performance of its larvae. Currently, the molecular mechanisms involved in the adaptation of E. sinensis larvae to a hyposaline environment remain unclear. Therefore, in this study, we designed an acute hyposaline stress experiment and sequenced the transcriptome and metabolome of the treated samples. After screening and annotation, 3323 and 2874 differentially expressed genes and 273 and 334 differentially expressed metabolites were identified by analysis of the transcriptomic data and metabolomic data at the megalopa and juvenile stages, respectively. Subsequently, a combined analysis of pathways was performed by co-mapping differentially expressed genes and differentially expressed metabolites into a KEGG database. Furthermore, the analysis results showed that 92 and 115 shared KEGG pathways were identified at the megalopa and juvenile stages, respectively. These shared pathways were mainly related to energy metabolism, osmotic pressure regulation, antioxidants, and immunity. The results showed that megalopa and juvenile had similar response mechanisms for adjusting to extremely hyposaline environments. The sudden drop in salinity may have impaired the osmoregulation ability and disturbed the energy metabolism of E. sinensis larvae. The glucose and TCA cycle processes were inhibited, and the cholesterol and glycine metabolisms were significantly changed. In addition, the sudden drop in salinity may cause oxidative stress in the larvae, accelerate the synthesis and consumption of glutathione, damage mitochondrial function, and induce cell apoptosis. Therefore, this study provides key information for understanding hyposaline tolerance mechanisms in E. sinensis larvae.

Tibial fracture surgery in elderly mice caused postoperative neurocognitive disorder via SOX2OT lncRNA in the hippocampus

Increasing evidence indicates the major role of mitochondrial function in neurodegenerative disease. However, it is unclear whether mitochondrial dynamics directly affect postoperative neurocognitive disorder (PND). This study aimed to analyze the underlying mechanisms of mitochondrial dynamics in the pathogenesis of PND. Tibial fracture surgery was performed in elderly mice to generate a PND model in vivo. Cognitive behavior was evaluated 3 days post-surgery using novel object recognition and fear conditioning. A gradual increase in the SOX2OT mRNA level and decrease in the SOX2 mRNA level were noted, with impaired cognitive function, in the mice 3 days after tibial surgery compared with mice in the sham group. To evaluate the role of SOX2OT in PND, SOX2OT knockdown was performed in vitro and in vivo using lentivirus transfection in HT22 cells and via brain stereotactic injection of lentivirus, respectively. SOX2OT knockdown reduced apoptosis, inhibited oxidative stress, suppressed mitochondrial hyperdivision, attenuated surgery-induced cognitive dysfunction, and promoted downstream SOX2 expression in elderly mice. Furthermore, Sox2 alleviated mitochondrial functional damage by inhibiting the transcription of mitochondrial division protein Drp1. Our study findings indicate that SOX2OT knockout alleviates surgery-induced mitochondrial fission and cognitive function defects by upregulating the expression of Sox2 in mice, resulting in the inhibition of drp1 transcription. Therefore, regulation of the SOX2/Drp1 pathway may be a potential mechanism for the treatment of patients with PND.

Multifunctional nanocomposites induce mitochondrial dysfunction and glucose deprivation to boost immunogenic ferroptosis for cancer therapy

Ferroptosis is a type of regulated cell death that has attracted much attention owing to its ability to trigger immunogenic cell death (ICD) and enhance immunotherapy. However, ferroptosis can be greatly limited by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms. Herein, to inhibit these antioxidant effects, therapeutic nanocomposites (Cu2−XS-GOx@CaCO3) were developed by attaching glucose oxidase (GOx) and mineralized calcium carbonate to the surface of hollow mesoporous copper sulfide (Cu2−XS, 0 < x < 1). Via GOx-mediated catalysis, intracellular glucose is oxidized to gluconic acid (GA) and hydrogen peroxide (H2O2). Notably, the generated GA stimulates the release of Ca2+ to damage mitochondrial function, while the produced H2O2 enhances the Fenton-like reaction triggered by Cu2−XS, and finally results in the accumulation of reactive oxygen species. Further, the depletion of glucose could damage the pentose phosphate pathway and hinder the synthesis of reduced glutathione (GSH) and the recycling of coenzyme Q10 (CoQ10) into reduced coenzyme Q10 (CoQ10H2), suggesting simultaneous inhibition of the GPX4/GSH and FSP1/CoQ10H2 pathways. Moreover, the accumulation of reactive oxygen species and the inhibition of antioxidant mechanisms could induce ferroptosis and ICD, followed by the recruitment of cytotoxic T lymphocytes, which synergistically provide an excellent anti-tumour effect. These findings provide a strong rationale for the application of ferroptosis-mediated immunotherapy.

Influence mechanism of tempering for storage quality of dried rice based on the evaluation of physicochemical and sensory characteristics and mitochondrial function and structure

Use of tempering has proven to be effective for the improvement of rice milling quality, but few researches focused on its influence mechanism for dried rice storage quality. In this study, influence mechanism of tempering treatments [tempering at 65 °C (DTHT), 50 °C (DTMT) and no tempering (DTNT)] on the storage quality of two varieties rice (“Aolongsimiao” and “Shengtaiyou 018″) was evaluated based on the assessment of physicochemical and sensory quality, and a novel method judging the damage of mitochondrial function and structure in dried rice. During rice drying and storage, compared with DTNT and DTMT samples, DTHT samples showed the slowest increase in fatty acid value (FAV), nonanoic acid (off-flavor compound) content, cooked rice hardness, cross-sectional crack, and ratio of broken rice. DTHT samples suffered less oxidative damage, maintained significantly (p < 0.05) higher mitochondrial antioxidant capacities (MAC) and membrane integrity, and showed a less than 18.18% increase of mitochondrial malondialdehyde (MDA). Mitochondrial super oxide dismutase and MDA were significant correlation (p < 0.01) with moisture content, FAV, appearance, texture, comprehensive score, and stickiness of rice quality. Tempering influence mechanism for rice storage quality might be its maintaining MAC and membrane integrity, and then inhibiting the decrease of dried rice storage quality.

SIRT3 ameliorates polycystic ovary syndrome through FOXO1/PGC-1α signaling pathway.

Current studies have shown that Sirtuin3 (SIRT3) plays a key role in oocyte maturation. Polycystic ovary syndrome (PCOS) is a common disease caused by endocrine and metabolic abnormalities. The specific regulatory role and mechanism of SIRT3 in PCOS have not been reported. SIRT3 was overexpressed in dihydrotestosterone (DHT)-induced PCOS model in mice. Ovary morphology, serum hormone level, and apoptosis of tissue cells were detected. The expression of SIRT3/Forkhead box protein O1 (FOXO1)/peroxlsome proliferator-activated receptor-γ coactlvat-1α (PGC-1α)-related proteins was detected. Then SIRT3 was overexpressed in DHT-induced human granulosa-like tumor cell line KGN. After the detection of the pathway-associated proteins, PGC-1α specific inhibitor SR-18292 was added to detect cell apoptosis, mitochondrial membrane potential, mitochondrial ROS (MitoROS) levels, and other mitochondrial-related indicators RESULTS: The expression of SIRT3 in PCOS model was significantly decreased. Overexpression of SIRT3 could significantly improve ovarian morphology and serum sex hormone levels in DHT-induced PCOS mice and inhibit apoptosis both in vitro and in vivo. Overexpression of SIRT3 also could improve mitochondrial dysfunction in DHT-induced KGN cells via FOXO1/PGC-1α signaling pathway. And PGC-1α inhibitor SR-18292 reversed the protective effect of SIRT3 overexpression on apoptosis and mitochondrial function damage of DHT-induced KGN cells. SIRT3 regulated FOXO1/PGC-1α signaling pathway to reduce mitochondrial dysfunction in PCOS, thereby improving PCOS.

Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

BackgroundDestruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis (RA). Acid-sensing ion channel 1a (ASIC1a) is a key molecule that mediates the destruction of RA articular cartilage. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear.MethodsWe treated rat articular chondrocytes with an acidic environment, analyzed the expression levels of mitochondrial stress protein HSP10, ClpP, LONP1 by q-PCR and immunofluorescence staining. Transmission electron microscopy was used to analyze the mitochondrial morphological changes. Laser confocal microscopy was used to analyze the Ca2+, mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) level. Moreover, ASIC1a specific inhibitor Psalmotoxin 1 (Pctx-1) and Ethylene Glycol Tetraacetic Acid (EGTA) were used to observe whether acid stimulation damage mitochondrial function through Ca2+ influx mediated by ASIC1a and whether pretreatment with estrogen could counteract these phenomena. Furthermore, the ovariectomized (OVX) adjuvant arthritis (AA) rat model was treated with estrogen to explore the effect of estrogen on disease progression.ResultsOur results indicated that HSP10, ClpP, LONP1 protein and mRNA expression and mitochondrial ROS level were elevated in acid-stimulated chondrocytes. Moreover, acid stimulation decreased mitochondrial membrane potential and damaged mitochondrial structure of chondrocytes. Furthermore, ASIC1a specific inhibitor PcTx-1 and EGTA inhibited acid-induced mitochondrial abnormalities. In addition, estrogen could protect acid-stimulated induced mitochondrial stress by regulating the activity of ASIC1a in rat chondrocytes and protects cartilage damage in OVX AA rat.ConclusionsExtracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the damage of rat articular chondrocytes. Estrogen antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. Our study provides new insights into the protective effect and mechanism of action of estrogen in RA.

Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats

Diosgenin (DIO) is a dietary and phytochemical steroidal saponin representing multiple activities. The present study investigated the protective effect of DIO on type II diabetes-associated nonalcoholic fatty liver disease (D-NAFLD). The rat model was established by high-fat diet and streptozotocin injection and then administered DIO for 8 weeks. The results showed that DIO reduced insulin resistance index, improved dyslipidemia, and relieved pancreatic damage. DIO decreased hepatic injury markers, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). H&E staining showed that DIO relieved hepatic lipid deposition. Mechanistically, DIO inhibited hepatic de novo lipogenesis (DNL) and increased fatty acid β-oxidation (FAO) through regulation of the AMPK-ACC/SREBP1 pathway. Endoplasmic reticulum (ER) stress was inhibited by DIO through regulation of PERK and IRE1 arms, which may then inhibit DNL. DIO also decreased reactive oxygen species (ROS) and enhanced the antioxidant capacity via an increase in Superoxide dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GPx) activities. The mitochondria are the site for FAO, and ROS can damage mitochondrial function. DIO relieved mitochondrial fission and fusion disorder by inhibiting DRP1 and increasing MFN1/MFN2 expressions. Mitochondrial apoptosis was then inhibited by DIO. In conclusion, the present study suggests that DIO protects against D-NAFLD by inhibiting DNL and improving FAO and mitochondrial function.

Exploring the mechanisms of neurotoxicity caused by fuzi using network pharmacology and molecular docking.

Safety has always been an important issue affecting the development of traditional Chinese medicine industry, especially for toxic medicinal materials, the establishment of risk prevention and control measures for toxic herbs is of great significance to improving the use of traditional Chinese medicine in clinical. Fuzi is a kind of traditional Chinese medicine and its toxicity has become the most important obstacle of limit in clinical using. In this paper, network pharmacology and molecular docking technology were used to analyze the main toxic components of Fuzi, the key targets and the mechanism of neurotoxicity. We carried out CCK-8 and WB assays, and detected LDH release and SDH activity. It was verified that aconitine caused neurotoxicity through a variety of pathways, including MAPK signaling pathway, pathways related to Akt protein, destruction of cell membrane integrity, damage of mitochondrial function affecting energy metabolism and apoptosis. What’s more, this study confirmed that aconitine could produce neurotoxicity by promoting apoptosis of hippocampus neuron and decreasing its quantity through Nissl Staining and TUNEL assay. This paper found and confirmed multiple targets and various pathways causing neurotoxicity of Fuzi, in order to provide reference for clinical application and related research.

P4HB UFMylation regulates mitochondrial function and oxidative stress

UFMylation is a ubiquitin-like modification which attaches the ubiquitin-fold modifier 1 to target proteins. To date, only a few UFMylation targets have been identified. In the current study, we demonstrated that P4HB is a new target protein for UFMylation and it can be UFMylated at three lysine residues in the form of mono-UFMylation. P4HB has oxidoreductase, chaperone and isomerase effects. It presents in the endoplasmic reticulum, mitochondria and cytosol. Next, we generated a stable HepG2 cell line, the hepatocellular cells, with defective P4HB UFMylation. Our data show that P4HB UFMylation defect promotes P4HB protein degradation via the ubiquitin-proteasome pathway. Defective P4HB UFMylation causes mitochondrial function damage, oxidative stress, and endoplasmic reticulum stress in HepG2 cells. These effects are more obvious when treating HepG2 cells with palmitic acid, which is frequently used as one of the cell models of non-alcoholic fatty liver disease (NAFLD). Our results identify UFMylation as a key post-translational modification for the maintenance of P4HB stability and biological functions in HepG2 cells, and point to P4HB UFMylation as a potential direction in the study of NAFLD.

Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping.

Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing more effective treatments. Current literature suggests toxins present in cigarette smoke and aerosolized e-vapor trigger abnormal intercellular responses, damage mitochondrial function, and consequently disrupt the homeostasis of the organelle’s biochemical processes by increasing reactive oxidative species. Increased oxidative stress sets off a cascade of molecular events, disrupting optimal mitochondrial morphology and homeostasis. Furthermore, smoking-induced oxidative stress may also amalgamate with other health factors to contribute to various pathophysiological processes. An increasing number of studies show that toxins may affect mitochondria even through exposure to secondhand or thirdhand smoke. This review assesses the impact of toxins present in tobacco smoke and e-vapor on mitochondrial health, networking, and critical structural processes, including mitochondria fission, fusion, hyper-fusion, fragmentation, and mitophagy. The efforts are focused on discussing current evidence linking toxins present in first, second, and thirdhand smoke to mitochondrial dysfunction.

Coix seed oil regulates mitochondrial functional damage to induce apoptosis of human pancreatic cancer cells via the PTEN/PI3K/AKT signaling pathway.

Coix seed oil (CSO) has a wide range of anticancer effects. However, the mechanism of action against pancreatic cancer (PC) and regulation of mitochondria in vitro is still unclear. This research investigated the possible mechanism of CSO induction of PC cell apoptosis and regulating mitochondrial functional damage. Proliferation of PC cells, mitochondrial membrane potential (MMP), qualitative and quantitative analysis of PC cell apoptosis, openness of mitochondrial permeability transition pore, related protein expression, generation of reactive oxygen species (ROS), and gene expression were determined by cell counting kit-8, JC-1 staining, acridine orange and ethidium bromide staining, flow cytometry, calcein-AM/cobalt staining, western blotting, dichlorofluorescein diacetate probe, and quantitative real-time reverse transcription-polymerase chain reaction, respectively. We confirmed that PTEN protein was involved in CSO-induced PANC-1 cell apoptosis and mitochondrial functional damage. CSO induced depolarization of MMP, increased opening of the mitochondrial permeability transition pore, increased ROS production, and further increased mitochondrial damage. Additionally, CSO downregulated expression of p-AKT and p-PI3K proteins; upregulated protein expression of cleaved caspase-9, Bax, cleaved caspase-3 and cytochrome c; and downregulated expression of Bcl-2 by upregulating the PTEN gene. The corresponding protein expression was consistent with the gene expression level. Furthermore, the loss of function of PTEN protein reduces the ability of CSO to induce apoptosis of PANC-1 cells and damage to mitochondrial function. CSO induces apoptosis of PANC-1 PC cells by modulating mitochondrial functional impairment and related apoptotic molecules via PTEN, which may be closely related to the PI3K/AKT signaling pathway.

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents.

Obesity, a metabolic disease caused by multiple factors, has become a global health problem. In addition to nutrient intake and sedentary lifestyle, environmental pollutants exposure has been shown to be involved in obesity epidemics. Antibiotics, a new type of environmental pollutant, have been widely used in animal husbandry, aquaculture and microorganism. However, the effects of antibiotics exposure on fat metabolism and metabolic diseases are largely unknown.Methods: We screened major types of antibiotics to examine their effects on the differentiation capacity and thermogenic functionality of brown and beige adipocytes, and found that azithromycin, one major kind of macrolide antibiotics suppressed brown and beige adipocyte functionality. We thus examined azithromycin accretion in adipose tissues of obese patients that correlates with BMI by high performance liquid chromatography-tandem mass spectrometry and systematically explore the influences of azithromycin on adiposity and metabolic performance in mice under high diet.Results: Azithromycin (macrolides) inhibits the mitochondrial and thermogenic gene programs of brown and beige adipocytes, thus disrupting their mitochondrial function and thermogenic response. Consistently, azithromycin treatment are more prone to diet-induced obesity in mice, and this was associated with impaired energy expenditure. Importantly, azithromycin is more accumulated in adipose tissue of obese patients and correlates with BMI and body weight. Mechanistically, we found that azithromycin inhibits mitochondria respiratory complex I protein levels and increases reactive oxidative species (ROS) levels, which causes damage of mitochondrial function in brown and beige adipocytes. The deleterious effects of azithromycin can be ameliorated by antioxidant N-acetyl-L-cysteine.Conclusions: Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.

Mitochondria Isolated from Hearts Subjected to Ischemia/Reperfusion Benefit from Adenine Nucleotide Translocase 1 Overexpression.

Reperfusion is the only feasible therapy following myocardial infarction, but reperfusion has been shown to damage mitochondrial function and disrupt energy production in the heart. Adenine nucleotide translocase 1 (ANT1) facilitates the transfer of ADP/ATP across the inner mitochondrial membrane; therefore, we tested whether ANT1 exerts protective effects on mitochondrial function during ischemia/reperfusion (I/R). The hearts of wild-type (WT) and transgenic ANT1-overexpressing (ANT1-TG) rats were exposed to I/R injury using the standard Langendorff technique, after which mitochondrial function, hemodynamic parameters, infarct size, and components of the contractile apparatus were determined. ANT1-TG hearts expressed higher ANT protein levels, with reduced levels of oxidative 4-hydroxynonenal ANT modifications following I/R. ANT1-TG mitochondria isolated from I/R hearts displayed stable calcium retention capacity (CRC) and improved membrane potential stability compared with WT mitochondria. Mitochondria isolated from ANT1-TG hearts experienced less restricted oxygen consumption than WT mitochondria after I/R. Left ventricular diastolic pressure (Pdia) decreased in ANT1-TG hearts compared with WT hearts following I/R. Preserved diastolic function was accompanied by a decrease in the phospho-lamban (PLB)/sarcoplasmic reticulum calcium ATPase (SERCA2a) ratio in ANT1-TG hearts compared with that in WT hearts. In addition, the phosphorylated (P)-PLB/PLB ratio increased in ANT1-TG hearts after I/R but not in WT hearts, which indicated more effective calcium uptake into the sarcoplasmic reticulum in ANT1-TG hearts. In conclusion, ANT1-TG rat hearts coped more efficiently with I/R than WT rat hearts, which was reflected by preserved mitochondrial energy balance, diastolic function, and calcium dynamics after reperfusion.