GLIDR-mediated regulation of tumor malignancy and cisplatin resistance in non-small cell lung cancer via the miR-342-5p/PPARGC1A axis.

BACKGROUND: Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a significant cause of cancer-related mortality, with drug resistance posing a substantial obstacle to effective therapy. LncRNAs have emerged as pivotal regulators of NSCLC progression, suggesting potential targets for cancer diagnosis and treatment. Therefore, identifying new lncRNAs as therapeutic targets and comprehending their underlying regulatory mechanisms are crucial for treating NSCLC. MATERIALS AND METHODS: RNA-sequencing data from 149 lung adenocarcinoma (LUAD) patients, including 130 responders and 19 nonresponders to primary treatment, were analyzed to identify the most effective lncRNAs. The effects and regulatory pathways of the selected lncRNAs on NSCLC and cisplatin resistance were investigated. RESULTS: Glioblastoma-downregulated RNA (GLIDR) was the most effective lncRNA in nonresponsive NSCLC patients undergoing primary treatment, and it was highly expressed in NSCLC patients and those with cisplatin-resistant NSCLC. Reducing GLIDR expression enhanced cisplatin sensitivity in resistant NSCLC and decreased the malignant characteristics of NSCLC. Moreover, bioinformatic analysis and luciferase assays revealed that microRNA-342-5p (miR-342-5p) directly targets GLIDR. MiR-342-5p overexpression inhibited NSCLC cell proliferation, migration, and invasion, whereas miR-342-5p inhibition promoted NSCLC malignancy, which was rescued by suppressing GLIDR. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPARGC1A) was identified as a downstream target of miR-342-5p. PPARGC1A inhibition increased cisplatin sensitivity in resistant NSCLC. Moreover, PPARGC1A inhibition suppresses NSCLC malignancy, whereas PPARGC1A overexpression promoted it. Furthermore, GLIDR overexpression was found to counteract the inhibitory effects of miR-342-5p on PPARGC1A, and increased PPARGC1A expression reversed the inhibition of NSCLC malignancies caused by decreased GLIDR. CONCLUSIONS: GLIDR is a prognostic marker for cisplatin treatment in NSCLC and a therapeutic target in cisplatin-resistant NSCLC. GLIDR promotes NSCLC progression by sponging miR-342-5p to regulate PPARGC1A expression and regulates cisplatin resistance through the miR-342-5p/PPARGC1A axis, underscoring its potential as a therapeutic target in cisplatin-resistant NSCLC.

The protective effects of chitosan and curcumin nanoparticles against the hydroxyapatite nanoparticles-induced neurotoxicity in rats.

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.

The interplay between BDNF and PGC-1 alpha in maintaining brain health: role of exercise.

Throughout our evolutionary history, physical activity has played a significant role in shaping our physiology. Advances in exercise science have further reinforced this concept by highlighting how exercise can change gene expression and molecular signaling to achieve various beneficial outcomes. Several studies have shown that exercise can alter neuronal functions to prevent neurodegenerative conditions like Parkinson's and Alzheimer's diseases. However, individual genotypes, phenotypes, and varying exercise protocols hinder the prescription of exercise as standard therapy. Moreover, exercise-induced molecular signaling targets can be double-edged swords, making it difficult to use exercise as the primary candidate for beneficial effects. For example, activating PGC-1 alpha and BDNF through exercise could produce several benefits in maintaining brain health, such as plasticity, neuronal survival, memory formation, cognition, and synaptic transmission. However, higher expression of BDNF might play a negative role in bipolar disorder. Therefore, further understanding of a specific mechanistic approach is required. This review focuses on how exercise-induced activation of these molecules could support brain health and discusses the potential underlying mechanisms of the effect of exercise-induced PGC-1 alpha and BDNF on brain health.

SIRT1 Regulates Mitochondrial Damage in N2a Cells Treated with the Prion Protein Fragment 106-126 via PGC-1α-TFAM-Mediated Mitochondrial Biogenesis.

Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106-126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106-126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106-126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106-126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.

The bacterial quorum sensing signal 2'-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2'-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages' mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway.

Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.

Tuning RXR Modulators for PGC1α Recruitment.

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.

The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

ZLN005, a PGC-1α Activator, Protects the Liver against Ischemia-Reperfusion Injury and the Progression of Hepatic Metastases.

BACKGROUND: Exercise can promote sustainable protection against cold and warm liver ischemia-reperfusion injury (IRI) and tumor metastases. We have shown that this protection is by the induction of hepatic mitochondrial biogenesis pathway. In this study, we hypothesize that ZLN005, a PGC-1α activator, can be utilized as an alternative therapeutic strategy. METHODS: Eight-week-old mice were pretreated with ZLN005 and subjected to liver warm IRI. To establish a liver metastatic model, MC38 cancer cells (1 × 106) were injected into the spleen, followed by splenectomy and liver IRI. RESULTS: ZLN005-pretreated mice showed a significant decrease in IRI-induced tissue injury as measured by serum ALT/AST/LDH levels and tissue necrosis. ZLN005 pretreatment decreased ROS generation and cell apoptosis at the site of injury, with a significant decrease in serum pro-inflammatory cytokines, innate immune cells infiltration, and intrahepatic neutrophil extracellular trap (NET) formation. Moreover, mitochondrial mass was significantly upregulated in hepatocytes and maintained after IRI. This was confirmed in murine and human hepatocytes treated with ZLN005 in vitro under normoxic and hypoxic conditions. Additionally, ZLN005 preconditioning significantly attenuated tumor burden and increased the percentage of intratumoral cytotoxic T cells. CONCLUSIONS: Our study highlights the effective protection of ZLN005 pretreatment as a therapeutic alternative in terms of acute liver injury and tumor metastases.

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.

Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.

Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.

Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Swimming alleviates myocardial fibrosis of type II diabetic rats through activating miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.

Myocardial fibrosis can trigger heart failure in diabetic cardiomyopathy (DCM), and irisin, an exercise-induced myokine, may have a beneficial effect on cardiac function. However, the specific molecular mechanism between exercise and irisin in the diabetic heart remains not fully explored. This study aimed to investigate how miR-34a mediates exercise-induced irisin to ameliorate myocardial fibrosis and its underlying mechanisms. Type 2 diabetes mellitus (T2DM) with DCM was induced in adult male rats with high-fat diet and streptozotocin injection. The DCM rats were subjected to swimming (60 min/d) and recombinant irisin (r-irisin, 500 µg/kg/d) interventions for 8 weeks, respectively. Cardiac function, cardiomyocyte structure, myocardial fibrosis and its correlated gene and protein expression were analyzed. Swimming intervention alleviated insulin resistance, myocardial fibrosis, and myocardial hypertrophy, and promoted blood glucose homeostasis in T2DM model rats. This improvement was associated with irisin upregulation and miR-34a downregulation in the myocardium, thus enhancing cardiac function. Similar efficacy was observed via intraperitoneal injection of exogenous recombinant irisin. Inhibition of miR-34a in vivo exhibited an anti-myocardial fibrotic effect by promoting irisin secretion through activating sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5) signal pathway and downregulating myocardial fibrosis markers (collagen I, collagen III, and transforming growth factor-ß1). Therefore, swimming-induced irisin has the potential therapeutic effect on diabetic myocardial fibrosis through activating the miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.

Chronic Stress-induced Serotonin Impairs Intestinal Epithelial Cell Mitochondrial Biogenesis via the AMPK-PGC-1α Axis.

Chronic stress is closely associated with gastrointestinal disorders. However, the impact of stress-related neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) on the intestines under chronic stress conditions remains poorly understood. This study aims to elucidate the mechanisms by which 5-HT affects mitochondrial biogenesis and intestinal barrier integrity during chronic stress. Employing a chronic restraint stress (CRS) mouse model, we observed elevated intestinal 5-HT levels, altered colonic mucosal structure, and disrupted tight junctions. The increase in 5-HT was associated with up-regulated serotonin synthesis enzymes and downregulated serotonin reuptake transporters, indicating an imbalance in serotonin homeostasis imbalance caused by chronic stress. Furthermore, serotonin exacerbated oxidative stress and impaired tight junction protein expression, highlighting its role in promoting intestinal barrier dysfunction. Experiments with cells in vitro demonstrated that 5-HT impairs mitochondrial biogenesis by inhibiting the AMPK-PGC-1α axis via 5-HT7 receptors and the cAMP-PKA pathway. Pharmacological inhibition of serotonin synthesis or 5-HT7 receptors alleviated the intestinal barrier damage caused by 5-HT and chronic stress, restoring mitochondrial biogenesis. These findings provide compelling evidence that serotonin exacerbates chronic stress-induced intestinal barrier disruption by inhibiting the AMPK-PGC-1α axis, paving the way for novel therapeutic interventions targeting the detrimental effects of serotonin on the intestine, particularly under chronic stress conditions.

[Inhibition of type 3 deiodinase expression can improve mitochondrial function in skeletal muscle of sepsis by up-regulating peroxisome proliferator-activated receptor-γ coactivator-1α].

OBJECTIVE: To investigate the protective effects and mechanisms of targeted inhibition of type 3 deiodinase (Dio3) on skeletal muscle mitochondria in sepsis. METHODS: (1) In vivo experiments: adeno-associated virus (AAV) was employed to specifically target Dio3 expression in the anterior tibial muscle of rats, and a septic rat model was generated using cecal ligation and puncture (CLP). The male Sprague-Dawley (SD) rats were divided into shNC+Sham group, shD3+Sham group, shNC+CLP group, and shD3+CLP group by random number table method, with 8 rats in each group. After CLP modeling, tibial samples were collected and Western blotting analysis was conducted to assess the protein levels of Dio3, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), and silence-regulatory protein 1 (SIRT1). Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was utilized to examine mRNA expression of genes including thyroid hormone receptors (THRα, THRß), monocarboxylate transporter 10 (MCT10), mitochondrial DNA (mtDNA), and PGC1α. Transmission electron microscopy was employed to investigate mitochondrial morphology. (2) In vitro experiments: involved culturing C2C12 myoblasts, interfering with Dio3 expression using lentivirus, and constructing an endotoxin cell model by treating cells with lipopolysaccharide (LPS). C2C12 cells were divided into shNC group, shD3 group, shNC+LPS group, and shD3+LPS group. Immunofluorescence colocalization analysis was performed to determine the intracellular distribution of PGC1α. Co-immunoprecipitation assay coupled with Western blotting was carried out to evaluate the acetylation level of PGC1α. RESULTS: (1) In vivo experiments: compared with the shNC+Sham group, the expression of Dio3 protein in skeletal muscle of the shNC+CLP group was significantly increased (Dio3/ß-Tubulin: 3.32±0.70 vs. 1.00±0.49, P < 0.05), however, there was no significant difference in the shD3+Sham group. Dio3 expression in the shD3+CLP group was markedly reduced relative to the shNC+CLP group (Dio3/ß-Tubulin: 1.42±0.54 vs. 3.32±0.70, P < 0.05). Compared with the shNC+CLP group, the expression of T3-regulated genes in the shD3+CLP group were restored [THRα mRNA (2-ΔΔCt): 0.67±0.05 vs. 0.33±0.01, THRß mRNA (2-ΔΔCt): 0.94±0.05 vs. 0.67±0.02, MCT10 mRNA (2-ΔΔCt): 0.65±0.03 vs. 0.57±0.02, all P < 0.05]. Morphology analysis by electron microscopy suggested prominent mitochondrial damage in the skeletal muscle of the shNC+CLP group, while the shD3+CLP group exhibited a marked improvement. Compared with the shNC+Sham group, the shNC+CLP group significantly reduced the number of mitochondria (cells/HP: 10.375±1.375 vs. 13.750±2.063, P < 0.05), while the shD3+CLP group significantly increased the number of mitochondria compared to the shNC+CLP group (cells/HP: 11.250±2.063 vs. 10.375±1.375, P < 0.05). The expression of mtDNA in shNC+CLP group was markedly reduced compared with shNC+Sham group (copies: 0.842±0.035 vs. 1.002±0.064, P < 0.05). Although no difference was detected in the mtDNA expression between shD3+CLP group and shNC+CLP group, but significant increase was found when compared with the shD3+Sham group (copies: 0.758±0.035 vs. 0.474±0.050, P < 0.05). In the shD3+CLP group, PGC1α expression was significantly improved at both transcriptional and protein levels relative to the shNC+CLP group [PGC1α mRNA (2-ΔΔCt): 1.49±0.13 vs. 0.68±0.06, PGC1α/ß-Tubulin: 0.76±0.02 vs. 0.62±0.04, both P < 0.05]. (2) In vitro experiments: post-24-hour LPS treatment of C2C12 cells, the cellular localization of PGC1α became diffuse; interference with Dio3 expression promoted PGC1α translocation to the perinuclear region and nucleus. Moreover, the acetylated PGC1α level in the shD3+LPS group was significantly lower than that in the shNC+LPS group (acetylated PGC1α/ß-Tubulin: 0.59±0.01 vs. 1.24±0.01, P < 0.05), while the expression of the deacetylating agent SIRT1 was substantially elevated following Dio3 inhibition (SIRT1/ß-Tubulin: 1.04±0.04 vs. 0.58±0.03, P < 0.05). When SIRT1 activity was inhibited by using EX527, PGC1α protein expression was notably decreased compared to the shD3+LPS group (PGC1α/ß-Tubulin: 0.92±0.03 vs. 1.58±0.03, P < 0.05). CONCLUSIONS: Inhibition of Dio3 in skeletal muscle reduced the acetylation of PGC1α through activating SIRT1, facilitating nuclear translocation of PGC1α, thereby offering protection against sepsis-induced skeletal muscle mitochondrial damage.

Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway.

BACKGROUND: Due to the complex pathophysiological mechanisms involved in cancer progression and metastasis, current therapeutic approaches lack efficacy and have significant adverse effects. Therefore, it is essential to establish novel strategies for combating cancer. Phytochemicals, which possess multiple biological activities, such as antioxidant, anti-inflammatory, antimutagenic, immunomodulatory, antiproliferative, anti-angiogenesis, and antimetastatic properties, can regulate cancer progression and interfere in various stages of cancer development by suppressing various signaling pathways. METHODS: The current systematic and comprehensive review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria, using electronic databases, including PubMed, Scopus, and Science Direct, until the end of December 2023. After excluding unrelated articles, 111 related articles were included in this systematic review. RESULTS: In this current review, the major signaling pathways of cancer metabolism are highlighted with the promising anticancer role of phytochemicals. This was through their ability to regulate the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. The AMPK/PGC-1α signaling pathway plays a crucial role in cancer cell metabolism via targeting energy homeostasis and mitochondria biogenesis, glucose oxidation, and fatty acid oxidation, thereby generating ATP for cell growth. As a result, targeting this signaling pathway may represent a novel approach to cancer treatment. Accordingly, alkaloids, phenolic compounds, terpene/terpenoids, and miscellaneous phytochemicals have been introduced as promising anticancer agents by regulating the AMPK/PGC-1α signaling pathway. Novel delivery systems of phytochemicals targeting the AMPK/PGC-1α pathway in combating cancer are also highlighted in this review.

MicroRNA-29b Plays a Vital Role in Podocyte Injury and Glomerular Diseases through Inducing Mitochondrial Dysfunction.

Diabetic kidney disease (DKD) is becoming the most leading cause of end-stage renal disease (ESRD). Podocyte injury plays a critical role in DKD progression. Notably, mitochondrial dysfunction is crucial for podocyte injury. MicroRNAs (miRNAs) involves in various kidney diseases. Herein, we discovered miR-29b was induced in the urine of 126 patients with DKD (stage I and II), and negatively correlated with kidney function and podocyte homeostasis. Mechanically, miR-29b targeted peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a co-activator of transcription factors regulating mitochondrial biogenesis and energy metabolism. In vitro, ectopic miR-29b downregulated PGC-1α and promoted podocyte injury, while inhibition of miR-29b alleviated podocyte injury. Consistently, inhibition of miR-29b mitigated podocyte injury and preserved kidney function in ADR nephropathy and db/db mice, and overexpression of miR-29b accelerated disease. Knockout miR-29b specifically in podocyte inhibited mitochondrial dysfunction and podocyte injury. These results revealed miR-29b plays a crucial role in mitochondrial dysfunction through targeted inhibition on PGC-1α, leading to podocyte injury and DKD progression. Importantly, miR-29b could serve as a novel biomarker of podocyte injury and assists to early diagnose DKD.

4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Objectives: The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease.Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.

Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics.

OBJECTIVE: Studies have shown that electroacupuncture (EA) can alleviate cognitive impairments from Alzheimer's disease (AD) by regulating the expression of adenosine monophosphate-activated protein kinase (AMPK), but the specific mechanism involved remains to be elucidated. Therefore, this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics. METHODS: The four-month-old transgenic mice with amyloid precursor protein (APP)/presenilin 1 (PS1) and AMPKα1-subunit conditional knockout (AMPKα1-cKO) were used for experiments. To evaluate the effects of EA treatment on cognitive function, the T-maze and Morris water maze were used. In addition, chemical exchange saturation transfer, thioflavin staining, transmission electron microscopy, mitochondrial membrane potential, and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice. RESULTS: Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment. Inactivation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway increased pathological amyloid-ß (Aß) deposition and aggravated the dysfunction in mitochondrial dynamics. In addition, EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1α pathway, specifically by reducing pathological Aß deposition, normalizing energy metabolism, protecting the structure and function of mitochondria, increasing the levels of mitochondrial fusion proteins, and downregulating the expression of fission proteins. However, the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout. CONCLUSION: The regulation of hippocampal mitochondrial dynamics and reduction in Aß deposition via the AMPK/PGC-1α pathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice. Please cite this article as: Jia WW, Lin HW, Yang MG, Dai YL, Ding YY, Xu WS, Wang SN, Cao YJ, Liang SX, Wang ZF, Chen C, Liu WL. Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics. J Integr Med. 2024; 22(5): 588-599.

Quercetin induces a slow myofiber phenotype in engineered human skeletal muscle tissues.

Skeletal muscle comprises slow and fast myofibers, with slow myofibers excelling in aerobic metabolism and endurance. Quercetin, a polyphenol, is reported to induce slow myofibers in rodent skeletal muscle both in vitro and in vivo. However, its effect on human myofiber types remains unexplored. In this study, we evaluated quercetin's impact on slow myofiber induction using human skeletal muscle satellite cells. In a two-dimensional culture, quercetin enhanced gene expression, contributing to muscle differentiation, and significantly expanded the area of slow-type myosin heavy chain positive cells. It also elevated the gene expression of Pgc1α, an inducer of slow myofibers. Conversely, quercetin did not affect mitochondrial abundance, fission, or fusion, but it did increase the gene expression of Cox7A2L, which aids in promoting mitochondrial supercomplexity and endurance, and Mb, which contributes to oxidative phosphorylation. In a three-dimensional culture, quercetin significantly extended the time to peak tension and half relaxation time of the engineered human skeletal muscle tissues constructed on microdevices. Moreover, quercetin enhanced the muscle endurance of the tissues and curbed the rise in lactate secretion from the exercised tissues. These findings suggest that quercetin may induce slow myofibers in human skeletal muscle.