Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate
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ABSTRACT:
PROVIDER: PRJNA1003090 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25556950.fastq.gz | Fastqsanger.gz | |||
| SRR25556951.fastq.gz | Fastqsanger.gz | |||
| SRR25556952.fastq.gz | Fastqsanger.gz | |||
| SRR25556953.fastq.gz | Fastqsanger.gz | |||
| SRR25556954.fastq.gz | Fastqsanger.gz |
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Project description:Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farensol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS farnesylation in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.
2023-08-12 | GSE240281 | GEO
Project description:Mitochondrial proteins and mitochondrial functions are interdependent. In this study, we confirm that the protein level of SFXN2 decreases significantly during mitochondrial damage, primarily due to proteasome-mediated degradation. Parkin, a mitochondrial E3 ligase, facilitates the polyubiquitination and proteasomal degradation of SFXN2. Reduced SFXN2 exacerbates mitochondrial damage‑induced cell death across multiple cell lines, while elevated expression of SFXN2 protects neurons from the mitochondrial stress. Taken together, this work identifies SFXN2, as a Parkin substrate, that mitigates mitochondrial damage and possesses anti‑apoptosis effect, and its reduction contributes to mitochondrial damage‑induced cell death in various cell lines, including 293T, SH‑SY5Y, and N2a cells.
2025-08-08 | GSE294872 | GEO
Project description:SFXN2 contributes mitochondrial dysfunction‑induced apoptosis as a substrate of Parkin
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Project description:In the opportunistic pathogen Candida albicans, hyphal growth and virulence factor expression are regulated by environmental and chemical cues. Farnesol is a secreted autoregulatory molecule that represses filamentation. It is derived from farnesyl pyrophosphate (FPP), an ergosterol biosynthesis pathway intermediate. Although Dpp1, Dpp2, and Dpp3 were proposed to synthesize farnesol, a mutant lacking all three had only a modest reduction in farnesol. To identify other farnesol biosynthesis genes, we employed transcription factor mutants that underproduced or overproduced farnesol in a screen and analyzed their transcriptomes. CWH8 was the only transcript correlated with farnesol production. Cwh8 is a lipid phosphatase known to recycle dolichyl pyrophosphate during glycosylation of cell wall proteins. The cwh8ΔΔ mutant had a >99% reduction in farnesol compared to the parent strain and was hyperfilamentous in embedded conditions. It had ~900-fold lower levels of farnesyl phosphate, the product of FPP dephosphorylation, suggesting Cwh8 acts directly on FPP. Complementation of the C. albicans cwh8ΔΔ mutant with CWH8 from C. albicans restored cell wall integrity and farnesol production. However, complementation with CWH8 from Clavispora lusitaniae, a species lacking farnesol signaling, restored cell wall integrity but failed to rescue farnesol production. This indicates that while Cwh8’s role in maintaining cell wall integrity is conserved, differences in substrate specificity or interactions with species-specific cofactors underlie its involvement in farnesol biosynthesis in C. albicans. Finally, fluconazole was fungicidal for cwh8ΔΔ rather than fungistatic. These studies demonstrate how an extracellular signaling system can arise and be co-opted to promote fungal fitness in complex environments.
2025-08-26 | GSE289051 | GEO
Project description:Purpose: The E3 ubiquitin ligase Parkin is a well-characterized regulator of mitochondrial autophagy (mitophagy); however, it is becoming increasingly appreciated to perform additional roles in various compartments of the cell. Our laboratory confirmed the presence of Parkin in the nucleus of various tissues (biochemical fractionations) and cell types (immunofluorescent imaging). Hypoxia-induced nuclear translocation of Parkin occured independent of the mitophagy regulator PINK1, and Parkinson's disease-associated mutants were restricted from the nuclueus. Accordingly, we inserted a nuclear localization sequence (NLS) at the n-terminus of Parkin and overexpressed both NLS Parkin and the wild-type protein in HeLa cells cultured at normoxia and hypoxia. Next-generation RNA-sequencing (RNA-seq) was used to determine the effect of nuclear Parkin on cellular transcription. Methods: mCherry-tagged NLS and wild-type Parkin were overexpressed in HeLa cells. Differential expression analyses were performed on Parkin vs. mCherry control cells and NLS Parkin vs. mCherry control cells at normoxia and following 12hr of hypoxia (n=3/group/condition). Paired-end sequencing was performed using the HiSeq4000. FastQC v0.11.3 was used for quality control, Trimmomatic v0.36 was used to trim reads which were aligned to the human genome (GRCh37.p13) using the STAR aligner v2.5.3a. Read quantification was performed with RSEM v 1.3.0 and the Gencode release 19. The R BioConductor packages edgeR and limma were used to implement the limma-voom method for differential expression analysis. Results: During normoxia, Parkin had no effect on basal transcription; however, overexpression of NLS Parkin was associated with 168 differentially expressed genes (DEGs: fold-change </= 1.5, FDR < 0.05) relative to mCherry control cells. Following hypoxia, the transcriptome associated with the overexpression of wild-type Parkin more closely resembled that of NLS Parkin. Along these lines, Parkin overexpression during hypoxia coincided with a total of 158 DEGs, 37% of which were shared with NLS Parkin. Overlapping and shared DEGs among Parkin and NLS Parkin were implicated in cellular metabolism, HIF1 signaling and survival. Our follow up co-immunoprecipitation and real-time quantitative PCR studies demonstrated that Parkin interacts with the Estrogen Related Receptor Alpha (ERRa) to promote the induction of its downstream target genes. Conclusions: Nuclear translocation of Parkin is a novel means by which this cytoprotective protein contributes to cellular homeostasis and especially critical during hypoxia.
2019-11-06 | GSE139989 | GEO
Project description:Gene expression profiles of Molt4 cells treated with DMCS (vehicle) or farnesol were compared to understand the mechanism by which farnesol induces apoptosis in these cells.
2014-05-01 | GSE46670 | GEO
Project description:The antifungal resistance threat posed by Candida auris necessitates bold and innovative therapeutic options. Farnesol, a quorum-sensing molecule with a potential antifungal and/or adjuvant effect; it may be a promising candidate in alternative treatment regimens. To gain further insights into the farnesol-related effect on C. auris, genome-wide gene expression analysis was performed using RNA-Seq. Farnesol exposure resulted in 1,766 differentially expressed genes. Of these, 447 and 304 genes with at least 1.5-fold increase or decrease in expression, respectively, were selected for further investigation. Genes involved in morphogenesis, biofilm events (maturation and dispersion), gluconeogenesis, iron metabolism, and regulation of RNA biosynthesis showed down-regulation, whereas those related to antioxidative defense, transmembrane transport, glyoxylate cycle, fatty acid β-oxidation, and peroxisome processes were up-regulated. In addition, farnesol treatment increased the expression of certain efflux pump genes, including MDR1, CDR1, and CDR2. Growth, measured by change in CFU number, was significantly inhibited within 2 hours of the addition of farnesol (5.8×10^7±1.1×10^7 and 1.1×10^7±0.3×10^7 CFU/ml for untreated control and farnesol-exposed cells, respectively) (p<0.001). In addition, farnesol treatment caused a significant reduction in intracellular iron (152.2±21.1 vs. 116.0±10.0 mg/kg), manganese (67.9±5.1 vs. 18.6±1.8 mg/kg), and zinc (787.8±22.2 vs. 245.8±34.4 mg/kg) (p<0.05–0.001) compared to untreated control cells, whereas the level of cooper was significantly increased (274.6±15.7 vs. 828.8±106.4 mg/kg) (p<0.001). Our data demonstrate that farnesol significantly influences the growth, intracellular metal ion contents, and gene expression related to fatty acid metabolism, which could open new directions in developing alternative therapies against C. auris.
2021-09-30 | GSE180093 | GEO
Project description:We used the results of a genome sequence survey to design and manufacture partial genomic microarrays that were applied to determining the transcriptional response of C. parapsilosis to the presence of exogenous farnesol. Keywords: drug response, farnesol,
2007-03-01 | GSE6318 | GEO
Project description:We used the results of a genome sequence survey to design and manufacture partial genomic microarrays that were applied to determining the transcriptional response of C. parapsilosis to the presence of exogenous farnesol. Keywords: drug response, farnesol, Transcriptional profiling was performed following exposure to 50 microM of farnesol compare to the control experiment (no treatment). Six independent experiment comparisons (including 3 dye swaps) were performed.
2010-06-11 | E-GEOD-6318 | biostudies-arrayexpress
Project description:Gene expression profiles of Molt4 cells treated with DMCS (vehicle) or farnesol were compared to understand the mechanism by which farnesol induces apoptosis in these cells. Molt4 cells were treated with 75 uM farnesol for 4 hrs to compare with vehicle-treated Molt4 cells. RNA from three replicates for each treatment was then isolated for microarray analysis.
2014-05-01 | E-GEOD-46670 | biostudies-arrayexpress