The ROS/SIRT1/STAR axis as a target for melatonin ameliorating atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells.

The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.

Differential effects of OATP2B1 on statin accumulation and toxicity in a beta cell model.

An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells via adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.

Early loss of endogenous NAD+ following rotenone treatment leads to mitochondrial dysfunction and Sarm1 induction that is ameliorated by PARP inhibition.

Sarm1 is an evolutionary conserved innate immune adaptor protein that has emerged as a primary regulator of programmed axonal degeneration over the past decade. In vitro structural insights have revealed that although Sarm1 induces energy depletion by breaking down nicotinamide adenine dinucleotide+ (NAD+ ), it is also allosterically inhibited by NAD+ . However, how NAD+ levels modulate the activation of intracellular Sarm1 has not been elucidated so far. This study focuses on understanding the events leading to Sarm1 activation in both neuronal and non-neuronal cells using the mitochondrial complex I inhibitor rotenone. Here, we report the regulation of rotenone-induced cell death by loss of NAD+ that may act as a 'biological trigger' of Sarm1 activation. Our study revealed that early loss of endogenous NAD+ levels arising due to PARP1 hyperactivation preceded Sarm1 induction following rotenone treatment. Interestingly, replenishing NAD+ levels by the PARP inhibitor, PJ34 restored mitochondrial complex I activity and also prevented subsequent Sarm1 activation in rotenone-treated cells. These cellular data were further validated in Drosophila melanogaster where a significant reduction in rotenone-mediated loss of locomotor abilities, and reduced dSarm expression was observed in the flies following PARP inhibition. Taken together, these observations not only uncover a novel regulation of Sarm1 induction by endogenous NAD+ levels but also point towards an important understanding on how PARP inhibitors could be repurposed in the treatment of mitochondrial complex I deficiency disorders.

Anesthetic Management of the Patient with Mitochondrial Disease: A Review of Current Best Evidence.

Anesthetic management of the patient with mitochondrial disease (MD) requires thoughtful preoperative planning and hypervigilant perioperative monitoring. MD affects 1 in 4,000 persons and is often an unfamiliar topic to the anesthesia provider. This review aims to inform the anesthetist on important considerations in perioperative management of MD. Patients with MD have impaired mitochondrial energy formation pathways affecting function of cardiac, central nervous, and musculoskeletal systems. All general anesthetics interfere with these mitochondrial bioenergetic pathways. MD patients exhibit hypersensitivity to volatile anesthetics. Propofol interferes with mitochondrial function via multiple pathways thus its use should be limited. MD is not at increased risk for malignant hyperthermia and should not be managed with prolonged propofol infusion. Succinylcholine is contraindicated due to hyperkalemia and myotonic risks. Nondepolarizing agents should be used with caution given unpredictable effects. No single anesthetic plan has been found to be safer than another in patients with MD. Intravenous and volatile anesthetics should be titrated incrementally while monitoring anesthetic depth clinically or via processed electroencephalogram (EEG). All MD patients should be optimized by minimizing fasting times, careful fluid selection to avoid lactate, and hypervigilant temperature management aimed at reducing the detrimental effects of catabolic stress during the perioperative period.

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we used C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. First, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse XFe96 Analyzer, we observed a detrimental effect of cisplatin and glucose on mitochondrial respiration. Second, because catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. Using a Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects against the dose-dependent neurotoxicity caused by cisplatin.

A novel role for vaping in mitochondrial gene dysregulation and inflammation fundamental to disease development.

We constructed and analyzed the whole transcriptome in leukocytes of healthy adult vapers (with/without a history of smoking), 'exclusive' cigarette smokers, and controls (non-users of any tobacco products). Furthermore, we performed single-gene validation of expression data, and biochemical validation of vaping/smoking status by plasma cotinine measurement. Computational modeling, combining primary analysis (age- and sex-adjusted limmaVoom) and sensitivity analysis (cumulative e-liquid- and pack-year modeling), revealed that 'current' vaping, but not 'past' smoking, is significantly associated with gene dysregulation in vapers. Comparative analysis of the gene networks and canonical pathways dysregulated in vapers and smokers showed strikingly similar patterns in the two groups, although the extent of transcriptomic changes was more pronounced in smokers than vapers. Of significance is the preferential targeting of mitochondrial genes in both vapers and smokers, concurrent with impaired functional networks, which drive mitochondrial DNA-related disorders. Equally significant is the dysregulation of immune response genes in vapers and smokers, modulated by upstream cytokines, including members of the interleukin and interferon family, which play a crucial role in inflammation. Our findings accord with the growing evidence on the central role of mitochondria as signaling organelles involved in immunity and inflammatory response, which are fundamental to disease development.

Role of mitochondria-endoplasmic reticulum coupling in lycopene preventing DEHP-induced hepatotoxicity.

Di (2-ethylhexyl) phthalate (DEHP) is a hazardous compound used as a plasticizer in plastic products. As a natural carotenoid, lycopene (LYC) is considered an effective protective agent against various types of organ damage. The present study aimed to investigate the role of mitochondria-endoplasmic reticulum (ER) coupling in LYC preventing DEHP-induced hepatotoxicity. The mice were treated with LYC (5 mg kg-1) and/or DEHP (500 or 1000 mg kg-1). In the present study, LYC prevented DEHP-induced histopathological changes including fibrosis and glycogen storage in the liver. Additionally, LYC alleviated DEHP-induced ultrastructural injury of mitochondria and ER. LYC had the underlying preventability against DEHP-induced mitochondrial dynamics imbalance including an increase in fission and a decrease in fusion. Furthermore, DEHP induced mitochondria-associated endoplasmic reticulum membrane (MAM) disorder-induced ER stress through the ER unfolded protein response (UPRER), but LYC alleviated these alterations. Therefore, LYC prevented DEHP-induced hepatic mitochondrial dynamics and MAM disorder, leading to ER stress. The present study provides novel evidence of mitochondria-ER coupling as a target for LYC that prevents DEHP-induced hepatotoxicity.

Calcium chelator BAPTA­AM protects against iron overload­induced chondrocyte mitochondrial dysfunction and cartilage degeneration.

Osteoarthritis (OA) is a common joint disease that is characterized by cartilage degradation. Iron deposition in the joints is common during the pathogenic progression of OA and recent studies have indicated that iron overload is an important contributor to OA progression. Calcium chelators have been reported to inhibit iron influx via modulating transferrin receptor protein 1 internalization, and they have been identified as a potential approach to the treatment of iron overload­induced diseases. The aim of the present study was to investigate the effect of calcium chelators on the progression of iron overload­induced OA. Primary chondrocytes were treated with various concentrations of ferric ammonium citrate (FAC) to mimic iron overload in vitro, followed by co­treatment with the calcium chelator BAPTA acetoxymethyl ester (BAPTA­AM). Subsequently, intracellular iron levels, cell viability, reactive oxygen species (ROS) levels, mitochondrial function and morphological changes, as well as MMP levels, were detected using commercial kits. It was demonstrated that FAC treatment significantly promoted chondrocyte apoptosis and the expression of MMPs, and these effects were reversed by co­treatment with BAPTA­AM. Moreover, BAPTA­AM suppressed iron influx into chondrocytes and inhibited iron overload­induced ROS production and mitochondrial dysfunction. These results indicated that calcium chelators may be of value in the treatment of iron metabolism­related diseases and iron overload­induced OA progression.

Kaempferol-3-O-rutinoside, a flavone derived from Tetrastigma hemsleyanum, suppresses lung adenocarcinoma via the calcium signaling pathway.

Lung cancer has been threatening human health worldwide for a long time. However, the clinic therapies remain unsatisfactory. In this study, the anti-adenocarcinoma lung cancer A549 cell line abilities of Tetrastigma hemsleyanum tuber flavonoids (THTF) were evaluated in vivo, and isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to detect the protein alterations in THTF-treated solid tumors. The differentially expressed proteins were related to the cytoskeleton and mostly accumulated in the calcium signaling pathway. The in vitro study illustrated that 80 µg mL-1 THTF significantly suppressed cellular viability to approximately 75% of the control. Further results suggested that kaempferol-3-O-rutinoside (K3R), the major component of THTF, effectively triggered cytoskeleton collapse, mitochondrial dysfunction and consequent calcium overload to achieve apoptosis, which remained consistent with proteomic results. This study uncovers a new mechanism for THTF anti-tumor ability, and suggests THTF and K3R as promising anti-cancer agents, providing new ideas and possible strategies for future anti-lung cancer prevention and therapy.

Oral Administration of Silibinin Ameliorates Cognitive Deficits of Parkinson's Disease Mouse Model by Restoring Mitochondrial Disorders in Hippocampus.

Besides motor disorder, cognitive dysfunction is also common in Parkinson's disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.

Exposure to oxidized soybean oil induces mammary mitochondrial injury in lactating rats and alters the intestinal barrier function of progeny.

Similar to other food contaminants, dietary oxidized soybean oil (OSO) is also a toxic xenobiotic for animal and human nutrition. This research evaluated the effects of maternal OSO exposure during lactation on mammary mitochondrial injury and intestinal barrier of sucking progeny. Twenty-four female adult SD rats were fed a fresh soybean oil (FSO) homozygous diet (7%) or an OSO homozygous diet (7%) during lactation. On day 21 of lactation, upregulated mRNA expression of Sirt3 and PRDX3 and downregulated mRNA expression of Mfn2 were observed in mammary tissues in the OSO group compared to the control group (P < 0.05). Maternal OSO consumption increased the FasL transcriptional level in the mammary glands of rat dams (P < 0.05), while the mRNA expression of Bax, Bcl-2, Caspase3, and Fas was not different from that in the control group (P > 0.05). OSO enhanced the Nrf2 transcriptional level and decreased the expression of Keap1 and PPARα in mammary tissues (P < 0.05). In addition, the contents of CAT, MDA, SOD were not affected by dietary OSO (P > 0.05), while the concentration of H2O2 was significantly decreased in the OSO-treated mammary glands of rat dams (P < 0.05). Maternal OSO exposure during lactation did not affect the organ coefficients of pups (P > 0.05). However, maternal OSO consumption influenced the intestinal tight junction protein expression of progeny (P < 0.05). In summary, the present study demonstrated that dietary OSO may aggravate mammary injury and mitochondria dysfunction, but the OSO-induced damage was self-alleviating via the promotion of Sirt3 and PRDX3 expression and further scavenging of oxidative products.

Mechanism of deoxynivalenol mediated gastrointestinal toxicity: Insights from mitochondrial dysfunction.

Deoxynivalenol (DON) is a mycotoxin predominantly produced by Fusarium genus, and widely contaminates cereals and associated products all over the world. The intestinal toxicity of DON is well established. However, intestinal homeostasis involves mitochondria, which has rarely been considered in the context of DON exposure. We summarize the recent knowledge on mitochondria as a key player in maintaining intestinal homeostasis based on their functions in cellular energy metabolism, redox homeostasis, apoptosis, intestinal immune responses, and orchestrated bidirectional cross-talk with gut microbe. In addition, we discuss the pivotal roles of mitochondrial dysfunction in the intestinal toxicity of DON and highlight promising mitochondrial-targeted therapeutics for DON-induced intestinal injury. Recent studies support that the intestinal toxicity of DON is attributed to mitochondrial dysfunction as a critical factor. Mitochondrial dysfunction characterized by failure in respiratory capacities and ROS overproduction has been demonstrated in intestinal cells exposed to DON. Perturbation of mitochondrial respiration leading to ROS accumulation is implicated in the early initiation of apoptosis. DON-induced intestinal inflammatory response is tightly linked to the mitochondrial ROS, whereas immunosuppression is intimately associated with mitophagy inhibition. DON perturbs the orchestrated bidirectional cross-talk between gut microbe and host mitochondria, which may be involved in DON-induced intestinal toxicity.

Isoflurane triggers the acute cognitive impairment of aged rats by damaging hippocampal neurons via the NR2B/CaMKII/CREB pathway.

Isoflurane was responsible for acute neuronal impairment, but its potential molecular mechanisms in damaging hippocampal neurons had not been clearly understood. This study aimed to explore the underlying mechanism of how isoflurane affected the cognitive function of aged rats by damaging the hippocampal neurons. Acute cognitive impairment was found in aged Wistar rats via Morris water maze test and Y-maze test after isoflurane anesthesia in a dose-dependent manner compared with the control group in vivo. Isoflurane also decreased the viabilities and strengthened the apoptotic potential of hippocampal neurons by damaging the mitochondria in a time-dependent manner compared with the control group which was reported by MTT, immunofluorescent assay, flow cytometry and western blot assay in vitro. Isoflurane jeopardized hippocampal neurons by directly inactivating the NR2B/CaMKII/CREB pathway and its harmful effects could be ameliorated by adding CaMKII activator CdCl2. These findings provided evidence that the cognitive ability of aged rats was injured by isoflurane exposure and isoflurane also inhibited the viability and enhanced the apoptosis of hippocampal neurons by damaging the mitochondria through inhibition of the NR2B/CaMKII/CREB pathway and its harmful roles could be partially ameliorated by CdCl2. Our study demonstrated that isoflurane could cause acute neuronal damage and we provided fresh insights that contributed to the safe use of anesthetic agents and the prevention of PND in elderly people.

Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson's Disease.

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD), particularly the inhibition of mitochondrial complex-I. This study aimed to evaluate the effect of fisetin in the rotenone-induced rat model of PD. Rotenone was administered (2 mg/kg s.c.) for 35 days to induce PD in animals. Fisetin was administered at two doses (10 mg/kg and 20 mg/kg p.o.) for 25 days to the animals that were given rotenone. Behavioral experiment, i.e. cylinder test, was performed to assess the motor asymmetry. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH) and catalase) and complex-I activity. In addition, histopathological studies were conducted. Fisetin treatment improved motor function in the cylinder test and reversed the rotenone-induced changes in mitochondrial enzymes, striatal dopamine levels, antioxidant enzyme levels and histological changes. An important finding of this study was both the doses of fisetin significantly (p < 0.05) enhanced rotenone-induced behavioral and biochemical changes and the effects were found to be dose dependent. Based on the present results, we hypothesize that fisetin may improve the mitochondrial enzyme activity, thereby preventing the pathogenesis of PD.

Increased ratio of P[v-a]CO2 to C[a-v]O2 without global hypoxia: the case of metformin-induced lactic acidosis.

The ratio of venoarterial CO2 tension to arteriovenous O2 content difference (P[v-a]CO2/C[a-v]O2) increases when lactic acidosis is due to inadequate oxygen supply (hypoxia); we aimed to verify whether it also increases when lactic acidosis develops because of mitochondrial dysfunction (dysoxia) with constant oxygen delivery. Twelve anaesthetised, mechanically ventilated pigs were intoxicated with IV metformin (4.0 to 6.4 g over 2.5 to 4.0 h). Saline and norepinephrine were used to preserve oxygen delivery. Lactate and P[v-a]CO2/C[a-v]O2 were measured every one or two hours (arterial and mixed venous blood). During metformin intoxication, lactate increased from 0.8 (0.6-0.9) to 8.5 (5.0-10.9) mmol/l (p < 0.001), even if oxygen delivery remained constant (from 352 ± 78 to 343 ± 97 ml/min, p = 0.098). P[v-a]CO2/C[a-v]O2 increased from 1.6 (1.2-1.8) to 2.3 (1.9-3.2) mmHg/ml/dl (p = 0.004). The intraclass correlation coefficient between lactate and P[v-a]CO2/C[a-v]O2 was 0.72 (p < 0.001). We conclude that P[v-a]CO2/C[a-v]O2 increases when lactic acidosis is due to dysoxia. Therefore, a high P[v-a]CO2/C[a-v]O2 may not discriminate hypoxia from dysoxia as the cause of lactic acidosis.

Muscle Stem Cell-Derived Extracellular Vesicles Reverse Hydrogen Peroxide-Induced Mitochondrial Dysfunction in Mouse Myotubes.

Muscle stem cells (MuSCs) hold great potential as a regenerative therapeutic but have met numerous challenges in treating systemic muscle diseases. Muscle stem cell-derived extracellular vesicles (MuSC-EVs) may overcome these limitations. We assessed the number and size distribution of extracellular vesicles (EVs) released by MuSCs ex vivo, determined the extent to which MuSC-EVs deliver molecular cargo to myotubes in vitro, and quantified MuSC-EV-mediated restoration of mitochondrial function following oxidative injury. MuSCs released an abundance of EVs in culture. MuSC-EVs delivered protein cargo into myotubes within 2 h of incubation. Fluorescent labeling of intracellular mitochondria showed co-localization of delivered protein and mitochondria. Oxidatively injured myotubes demonstrated a significant decline in maximal oxygen consumption rate and spare respiratory capacity relative to untreated myotubes. Remarkably, subsequent treatment with MuSC-EVs significantly improved maximal oxygen consumption rate and spare respiratory capacity relative to the myotubes that were damaged but received no subsequent treatment. Surprisingly, MuSC-EVs did not affect mitochondrial function in undamaged myotubes, suggesting the cargo delivered is able to repair but does not expand the existing mitochondrial network. These data demonstrate that MuSC-EVs rapidly deliver proteins into myotubes, a portion of which co-localizes with mitochondria, and reverses mitochondria dysfunction in oxidatively-damaged myotubes.

S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle.

Mitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration. Mitochondria-targeted antioxidants, such as MitoQ, have emerged as potentially effective antioxidant therapies. Methionine sulfoxide reductase A (MsrA) is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine (Met)-centered redox cycle (MCRC). In this study, we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells. This antioxidation was largely dependent on the Met oxidase activity of MsrA. S-methyl-L-cysteine (SMLC), a natural analogue of Met that is abundantly found in garlic and cabbage, could activate the Met oxidase activity of MsrA to scavenge free radicals. Furthermore, SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Thus, our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.

Resveratrol ameliorates disorders of mitochondrial biogenesis and mitophagy in rats continuously exposed to benzo(a)pyrene from embryonic development through adolescence.

Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats.

Astaxanthin attenuates d-galactose-induced brain aging in rats by ameliorating oxidative stress, mitochondrial dysfunction, and regulating metabolic markers.

Astaxanthin (AX) is a red-colored xanthophyll carotenoid with potent antioxidant, anti-inflammatory, and neuroprotective properties. However, the underlying in vivo mechanism by which AX protects the brain from oxidative stress remains unclear. In this study, we investigated the protective effect of AX on brain oxidative damage in a d-galactose-induced rat model of aging. We also explored its possible mechanism of action by analyzing the resulting serum metabolic profiles. Our results showed that AX significantly increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) by 26%, 30%, and 53%, respectively. AX also significantly increased the mitochondrial membrane potential by 18% when compared with the model group. Additionally, treatment with AX (15 mg kg-1) increased the activities of respiratory chain complexes I and IV by 50.17% and 122.87%, respectively. Furthermore, AX also improved age-related morphological changes in the cerebral cortex and hippocampus. Significant differences in serum metabolic profiles were observed between the d-galactose and AX treatment groups. AX corrected amino acid metabolic problems by increasing the levels of N-acetyl-l-leucine, N-acetyl-l-tyrosine, and methionine sulfoxide to protect nerve cells. This also allowed AX to regulate the pentose phosphate pathway by acting on ergotoxine, d-xylose-5-phosphoric, and thiamine, to against oxidative stress and apoptosis. Moreover, AX reduced the levels of both hyodeoxycholic acid and chenodeoxycholic acid though the primary bile acid biosynthesis pathway, resulting in improved brain mitochondrial dysfunction. In conclusion, AX likely enhances the brain's antioxidant defenses through these potential metabolic means, enabling the brain to resist mitochondrial dysfunction, improve neuronal damage, and protect the electron transmission of mitochondrial respiratory chain, thus preventing brain aging.