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Cell Death & Disease Jun 2024The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial...
The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.
Topics: Glioblastoma; Humans; Transforming Growth Factor beta; Animals; Signal Transduction; Disease Progression; Cell Line, Tumor; Integrin alphaV; Mice; Brain Neoplasms; Cell Movement; Mice, Nude; Receptor, Transforming Growth Factor-beta Type I; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic
PubMed: 38942749
DOI: 10.1038/s41419-024-06790-8 -
Molecular Genetics and Metabolism Jun 2024Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary...
Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.
PubMed: 38941880
DOI: 10.1016/j.ymgme.2024.108516 -
Journal of Cell Science Jun 2024Mitochondrial biogenesis relies on hundreds of proteins that are derived from genes encoded in the nucleus. According to characteristic properties of N-terminal...
Mitochondrial biogenesis relies on hundreds of proteins that are derived from genes encoded in the nucleus. According to characteristic properties of N-terminal targeting peptides (TP) and multi-step authentication by the protein translocase called the TOM complex, nascent polypeptides satisfying the requirements are imported into mitochondria. However, it is unknown whether eukaryotic cells with a single mitochondrion per cell have a similar complexity of presequence requirements for mitochondrial protein import compared to other eukaryotes with multiple mitochondria. Based on putative mitochondrial TP sequences in the unicellular red alga Cyanidioschyzon merolae, we designed synthetic TPs (synTPs) and showed that functional TPs must have at least one basic residue and a specific amino acid composition, although their physicochemical properties are not strictly determined. Combined with the simple composition of the TOM complex in C. merolae, our results suggest that a regional positive charge in TP is verified solely by TOM22 for mitochondrial protein import in C. merolae. The simple authentication mechanism indicates that the monomitochondrial C. merolae does not need to increase the cryptographic complexity of the lock-and-key mechanism for mitochondrial protein import.
PubMed: 38940185
DOI: 10.1242/jcs.262042 -
Frontiers in Bioscience (Landmark... Jun 2024The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by... (Review)
Review
The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by the accumulation of misfolded proteins, elevated reactive oxygen species (ROS) levels, and abnormal Ca2+ signaling, which was referred to ER stress (ERS). Ferroptosis was a unique programmed cell death model mediated by iron-dependent phospholipid peroxidation and multiple signaling pathways. The changes of mitochondrial structure, the damage of glutathione peroxidase 4 (GPX4) and excess accumulation of iron were the main characteristics of ferroptosis. ROS produced by ferroptosis can interfere with the activity of protein-folding enzymes, leading to the accumulation of large amounts of unfolded proteins, thus causing ERS. On the contrary, the increase of ERS level could promote ferroptosis by the accumulation of iron ion and lipid peroxide, the up-regulation of ferroptosis related genes. At present, the studies on the relationship between ferroptosis and ERS were one-sided and lack of in-depth studies on the interaction mechanism. This review aimed to explore the molecular mechanism of cross-talk between ferroptosis and ERS, and provide new strategies and targets for the treatment of liver diseases.
Topics: Ferroptosis; Humans; Endoplasmic Reticulum Stress; Liver Diseases; Reactive Oxygen Species; Animals; Signal Transduction; Iron; Lipid Peroxidation; Endoplasmic Reticulum
PubMed: 38940044
DOI: 10.31083/j.fbl2906221 -
Frontiers in Bioscience (Landmark... Jun 2024This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated...
BACKGROUND
This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth.
METHODS
The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between expression and its downstream genes was analyzed in a melanoma tissue array.
RESULTS
TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between expression and the expression of , , and . Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth.
CONCLUSIONS
TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.
Topics: Humans; Endoplasmic Reticulum Stress; Melanoma; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Cell Death; Apoptosis; Cell Proliferation; Membrane Proteins
PubMed: 38940043
DOI: 10.31083/j.fbl2906233 -
Frontiers in Bioscience (Landmark... Jun 2024This study investigated the impact of salvianolic acids, derived from Danshen, on melanoma cell growth. Specifically, we assessed the ability of salvianolic acid A (Sal...
BACKGROUND
This study investigated the impact of salvianolic acids, derived from Danshen, on melanoma cell growth. Specifically, we assessed the ability of salvianolic acid A (Sal A) to modulate melanoma cell proliferation.
METHODS
We used human melanoma A2058 and A375 cell lines to investigate the effects of Sal A on cell proliferation and death by measuring bromodeoxyuridine incorporation and lactate dehydrogenase release. We assessed cell viability and cycle progression using water soluble tetrazolium salt-1 (WST-1) mitochondrial staining and propidium iodide. Additionally, we used a phospho-kinase array to investigate intracellular kinase phosphorylation, specifically measuring the influence of Sal A on checkpoint kinase-2 (Chk-2) via western blot analysis.
RESULTS
Sal A inhibited the growth of A2058 and A375 cells dose-responsively and induced cell cycle arrest at the G2/M phase. Notably, Sal A selectively induces Chk-2 phosphorylation without affecting Chk-1, thereby degrading Chk-2-regulated genes and . However, Sal A does not affect the Chk1-Cdc25C pathway.
CONCLUSIONS
Salvianolic acids, especially Sal A, effectively hinder melanoma cell growth by inducing Chk-2 phosphorylation and disrupting G2/M checkpoint regulation.
Topics: Humans; Checkpoint Kinase 2; cdc25 Phosphatases; Melanoma; Cell Line, Tumor; Cell Proliferation; Lactates; Caffeic Acids; Signal Transduction; Phosphorylation; Cell Survival
PubMed: 38940031
DOI: 10.31083/j.fbl2906213 -
Biomaterials Science Jun 2024The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of...
The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable -organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The -organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.
PubMed: 38939985
DOI: 10.1039/d4bm00583j -
Mitochondrial DNA. Part B, Resources 2024Lendn. 1930 has been widely used in food fermentation; however, its mitochondrial genome characteristics are not well understood. In this study, the complete...
Lendn. 1930 has been widely used in food fermentation; however, its mitochondrial genome characteristics are not well understood. In this study, the complete mitochondrial genome of was obtained, which was 61,400 bp in length with a GC content of 33%. The mitochondrial genome was found to contain 14 core protein-coding genes, four free-standing ORFs, 18 intronic ORFs, 26 tRNAs, and two rRNA genes. Phylogenetic trees were generated for 25 early-differentiated fungi using the Bayesian inference (BI) method, which demonstrated that is closely related to . This study provides useful information for the classification and evolution of species or other early-differentiated fungi.
PubMed: 38939449
DOI: 10.1080/23802359.2024.2371376 -
Frontiers in Pediatrics 2024The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial...
The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial DNA (mtDNA) copy number (mtDNAcn), a key mitochondrial change associated with chronic stress, is an emerging biomarker for disease pathology and progression. mtDNAcn can be quantified from whole blood samples using qPCR to determine the ratio of mtDNA to nuclear DNA. However, the collection of blood samples in pediatric populations, particularly in infants and young children, can be technically challenging, yield much smaller volume samples, and can be distressing for the patients and their caregivers. Therefore, we have validated a mtDNAcn assay utilizing DNA from simple buccal swabs (Isohelix SK-2S) and report here it's performance in specimens from infants (age = <12 months). Utilizing qPCR to amplify ∼200 bp regions from two mitochondrial () and two nuclear () genes, we demonstrated absolute (100%) concordance with results from low-pass whole genome sequencing (lpWGS). We believe that this method overcomes key obstacles to measuring mtDNAcn in pediatric populations and creates the possibility for development of clinical assays to measure mitochondrial change during pathophysiological stress.
PubMed: 38938506
DOI: 10.3389/fped.2024.1401737 -
Animal Bioscience Jun 2024Somatostatin (SS) plays important regulatory roles in animal growth and reproduction by affecting the synthesis and secretion of growth hormone (GH). However, the...
OBJECTIVE
Somatostatin (SS) plays important regulatory roles in animal growth and reproduction by affecting the synthesis and secretion of growth hormone (GH). However, the mechanism by which SS regulates growth and development in goats is still unclear.
METHODS
In this study, we randomly selected eight 7-month-old Dazu black goats (DBGs) of similar body weight and equally assigned four bucks as the immunised and negative control groups. The immunised group received the Salmonella typhi attenuated vaccine CSO22 (ptCS/2SS-asd) orally, whilst the negative control group received the empty vector vaccine CSO22 (pVAX-asd) orally.
RESULTS
The SS concentration in the serum of goats in the immunised group was significantly lower than that in the negative control group, and the daily gain was significantly higher (p < 0.05). SS-14 DNA vaccine immunisation resulted in significantly higher concentrations of growth-related hormones such as GH-releasing hormone and IGF-1 in the serum of goats (p < 0.05). RNA-seq analysis of hypothalamus of oral SS-14 DNA vaccine and negative control DBGs identified 31 differentially expressed genes (DEGs). Pituitary gland identified 164 DEGs. A total of 246 DEGs were detected in the liver by RNA-seq. Gene ontology (GO) of DEGs was enriched in mitochondrial envelope, extracellular region, receptor binding and cell proliferation. The biological metabolic pathways associated with DEGs were explored by Kyoto Encyclopedia of Genes and Genomes analysis. DEGs were associated with metabolic pathways, oxidative phosphorylation, vitamin digestion and absorption and galactose metabolism. These candidate genes (e.g. DGKK, CYTB, DUSP1 and LRAT) may provide references for exploring the molecular mechanisms by which SS promotes growth and development.
CONCLUSION
Overall, these results demonstrated that the SS DNA vaccine enhanced the growth of DBGs by altering growth-related hormone concentrations and regulating the expression of growth-related genes in the hypothalamic-pituitary-liver axis.
PubMed: 38938026
DOI: 10.5713/ab.24.0121