Inhibition of mitochondrial transcription by the neurotoxin MPP+
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA884437 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21719761.fastq.gz | Fastqsanger.gz | |||
| SRR21719762.fastq.gz | Fastqsanger.gz | |||
| SRR21719763.fastq.gz | Fastqsanger.gz | |||
| SRR21719764.fastq.gz | Fastqsanger.gz | |||
| SRR21719765.fastq.gz | Fastqsanger.gz |
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Project description:The neurotoxin MPP+ triggers cell death of dopamine neurons and induces Parkinson’s disease symptoms in mice and men, but the immediate transcriptional response to this neurotoxin has not been studied. We therefore treated human SH-SY5Y cells with a low dose (0.1 mM) of MPP+ and measured the effect on nascent transcription by precision run-on sequencing (PRO-seq). We found that transcription of the mitochondrial genome was significantly reduced already after 30 min, whereas nuclear gene transcription was unaffected. Inhibition of respiratory complex I by MPP+ led to reduced ATP production, that may explain the diminished activity of mitochondrial RNA polymerase. Our results show that MPP+ has a direct effect on mitochondrial function and transcription, and that other gene expression or epigenetic changes induced by this neurotoxin are secondary effects that reflect a cellular adaptation program.
2023-06-01 | GSE214243 | GEO
Project description:The majority of mitochondrial preproteins is targeted via N-terminal presequences that are cleaved upon import into the organelle. The essential mitochondrial processing protease (MPP) is assumed to cleave the majority of incoming precursors. However, only few substrate proteins of MPP have been experimentally determined and analysis of a broad range of substrates is missing so far. Here, we present the first systematic approach to identify substrate proteins of MPP. We used a temperature-sensitive mutant of the MPP subunit Mas1 grown at non-permissive temperature. Analysis of highly purified mitochondria by quantitative N-terminal ChaFRADIC led to the identification of 85 potential MPP substrate proteins. Deduction of the cleaved presequences shows that arginine in position -2 is the main determinant of MPP recognition. Interestingly, several non-processed proteins were increased in mas1 mutant mitochondria revealing a novel mitochondrial proteotoxic stress response that ultimately leads to an increased membrane potential presumably to balance/compensate the impairment of the major presequence processing peptidase.
2015-10-14 | PXD002063 | Pride
Project description:Parkinson’s disease (PD) is a common neurodegenerative disease, which associated with oxidative stress. Due to the antioxidant function of Selenium (Se), it may have a neuroprotective function in PD. Nevertheless, the Se involved and its role in the protective function is still unclear. 1-methyl-4-phenylpyridinium (MPP+), which inhibits mitochondrial respiration, is usually used to produce a reliable PD cellular model. In this study, we discovered that Se could modulate cytotoxicity in MPP+ induced PD model and used genome wide high throughput sequencing to capture the gene expression profiles of MPP+ treatment PC12 cells with or without Se. We identified 351 differentially expressed mRNAs (DEGs) and 14 differentially expressed long non-coding RNAs (DELs) in MPP+ group vs. normal control group, 244 DEGs and 27 DELs in Se + MPP+ group vs. MPP+ group. Functional annotation analysis of DEGs and DELs cis-target genes revealed that they were enriched in reactive oxygen species (ROS) metabolic process and mitochondrial control of apoptosis. Our data suggests that DEGs, Txnrd1, siglec1 and Klf2, and the DEL AABR07044454.1 cis-acting on target gene Cdkn1a, may act a protective function in PD model. For the first time, our study systematically demonstrated that mRNAs and lncRNAs induced by Se involved in neuroprotection in PD and provided new insight into how Se modulates cytotoxicity in MPP+ induced PD model.
2024-10-27 | GSE186702 | GEO
Project description:Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibition
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Project description:Idiopathic Parkinson’s disease (iPD) and manganese-induced atypical Parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to L-DOPA differentiate both, the differences at the neuronal level are largely unknown. We investigated the morphological, physiological and molecular differences in dopaminergic neurons exposed to the PD toxin 1-methyl-4-phenylpyridinium ion (MPP+) and manganese (Mn). While Mn was neurotoxic at lower dose, MPP+ toxicity entailed oxidative damage, mitochondria dysfunction and glycolytic shift. Morphological analysis highlighted mitochondrial damage, while morphometric analysis indicated loss of neuronal processes in the MPP+ model and not in the Mn model. Elecrophysiological analysis demonstrated lower number of spikes and firing frequency in MPP+ treated cells, while it was unchanged in the Mn model. High throughput transcriptomic analysis revealed upregulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic and mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeletal architecture. Analysis of the JAK-STAT pathway with implications for neuritogenesis, neuronal proliferation and nuclear function revealed contrasting profile between Mn and MPP+ models. Genome-wide DNA methylation profile revealed significant differences between both models and substantiated the epigenetic basis of the difference in the JAK-STAT pathway. We conclude that iPD and atypical Parkinsonism represent a divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and to evolve novel therapeutics
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Project description:Impaired dopamine homeostasis is an early event in the pathogenesis of Parkinson's disease. Generation of intracellular reactive oxygen species consequent to dopamine oxidation leads to mitochondrial dysfunction and eventually cell death. Alterations in the mitochondrial proteome due to dopamine exposure were investigated in the SH-SY5Y human neuroblastoma cell line. The combination of two orthogonal proteomic approaches, two-dimensional electrophoresis and shotgun proteomics, was used to highlight the specific pathways perturbed by the increase of intracellular dopamine, in comparison with those perturbed by a specific mitochondrial toxin (4-methyphenylpyridinium, MPP+), a neurotoxin causing Parkinsonism-like symptoms in animal models. Proteins altered by MPP+ did not completely overlap with those affected by dopamine treatment. In particular, the MPP+ target complex I component NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 was not affected by dopamine together with 26 other proteins. The comparison of proteomics approaches highlighted the fragmentation of some mitochondrial proteins, suggesting an alteration of the mitochondrial protease activity. Pathway and disease association analysis of the proteins affected by dopamine revealed the overrepresentation of the Parkinson's disease and the parkin-ubiquitin proteasomal system pathways and of gene ontologies associated to generation of precursor metabolites and energy, response to topologically incorrect proteins and programmed cell death. These alterations may be globally interpreted in part as the result of a direct effect of dopamine on mitochondria (e.g. alteration of the mitochondrial protease activity) and in part as the effect on mitochondria of a general activation of cellular processes (e.g. regulation of programmed cell death).
2014-04-15 | PXD000838 | Pride
Project description:Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Apart from the proteostasis response, whether and how other mechanisms contribute to lifespan extension upon mitochondrial translation inhibition is underexplored. Using multi-omics and functional in vivo screening, we identified the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as essential for mitochondrial translation inhibition-induced longevity. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition while mitochondrial unfolded protein response activation is unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Additionally, we discovered that sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the “immuno-metabolic stress responses” in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
2025-04-23 | GSE248642 | GEO
Project description:The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.
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Project description:Pairwise comparisons of purified mouse LT-HSC, ST-HSC and MPP.
2005-09-09 | E-SMDB-3457 | biostudies-arrayexpress