Transriptional effects of blocking mitochondrial fission-fusion in aging Drosophila clock neurons
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE275587 | GEO | 2025/10/17
REPOSITORIES: GEO
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Project description:Transriptional effects of blocking mitochondrial fission-fusion in aging Drosophila clock neurons
| PRJNA1151715 | ENA
Project description:Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.
2016-08-25 | PXD004890 | Pride
Project description:Animals must be able to engage pleiotropic immune defense mechanisms against microorganisms to survive infection. Here we reveal an unexpected function for mitochondrial fission in innate immunity, showing this process mediates host defense through antimicrobial lipid droplet production. Bacterial infection activates fission, enabling microbial clearance in mammalian macrophages and Caenorhabditis elegans. The mechanism involves the mitochondrial unfolded protein response (UPRmt), characterized by activation of Atf transcription factor family members in mouse (Atf5) and C. elegans (ATFS-1). Fission and the UPRmt initiate bacterial killing through inducible production of lipid droplets, organelles with antimicrobial properties. Salmonella enterica serovar Typhimurium blocks inducible fission but inhibiting the fusion-promoting enzyme histone deacetylase 6 (Hdac6) overcomes this host subversion, enabling bacterial clearance. We propose that mitochondrial fission has similarities to intracellular bacterial replication, forewarning the host of impending infection. Awakening this ancient pathway in bacterial pathogen-compromised cells could be exploited for host-directed anti-infective strategies.
2025-11-30 | GSE225734 | GEO
Project description:Mitochondria are highly dynamic organelles undergoing fusion, fission and degradation. Although mitochondria are known to be essential for cellular metabolism, it is not fully understood how mitochondrial dynamics affect cellular metabolism. We previously identified a mouse gene, transmembrane protein 135 (TMEM135) that plays a role in the regulation of mitochondrial dynamics. Mice with mutant Tmem135 (Tmem135FUN025/FUN025) show accelerated aging phenotypes and age-related pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene (Tmem135 TG). In several tissues and cells that we studied such as the retina, heart and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while over-expression of Tmem135 results in fragmented mitochondria. These unique mouse models allow us to test how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells. In this study, we identified metabolic changes in primary RPE cell cultures as well as tissues isolated from Tmem135FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance (NMR) spectroscopy. Metabolomics analysis revealed a tissue-dependent response to alterations to Tmem135 whereby, significant metabolic changes were observed in heart in both mutant and TG mice as compared to WT while negligible effects were observed in cerebellum and hippocampus. We also observed changes in Tmem135FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis, glucose metabolism and phospholipid metabolism. Significant depletion of NAD+ was detected in both Tmem135FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD+ level. Thus, we have identified metabolomic changes associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities.
2021-02-12 | MTBLS1410 | MetaboLights
Project description:Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.
2023-05-15 | PXD041990 | Pride
Project description:<p>The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia towards the pro - inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.</p>
2025-12-23 | MTBLS13564 | MetaboLights
Project description:Mitotic fission is increased in hyperproliferative, apoptosis-resistant diseases, such as pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype includes activation of the fission mediator, dynamin related protein 1 (Drp1), which must complex with its adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore the role of their dysregulation in the pathogenesis of PAH. MiDs are increased in PAH PASMC. This accelerates Drp1-mediated mitotic fission, which increases cell proliferation and decreases apoptosis. Silencing MiDs (but not Fis1 or MFF) promotes mitochondrial fusion and G1-phase cell cycle arrest through an ERK1/2 and CDK4-dependent mechanism. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased microRNA-34a-3p (miR-34a-3p) expression. Circulatory miR34a-3p expression is decreased in PAH patients as well as in preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. We used microarrays to identify differences in miR expression in pulmonary artery smooth muscle cells (PASMC) taken from either pulmonary arterial hypertension patients or healthy controls
2018-01-31 | GSE108707 | GEO
Project description:Ectopic ATP synthase is a functional onco-protein increases cell proliferation when transported to plasma membrane of cancer cells. Our previous study performed large scale gene silencing screening indicated ER and mitochondrial transport pathways may lead to ectopic ATP synthase expression. Silencing dynamin-related protein 1 (Drp1), mitofusin-1 (Mfn1) and Parkin affected ectopic ATP synthases expression. However, the underlying trafficking mechanism is poorly understood. Here, we analyzed our membrane and mitochondrial proteome of lung cancer A549 cells and found that both nuclear-encoded ATP synthase subunits and mitochondrial-encoded components-ATP6 translocated to cell surface, indicating that ATP synthase subunits assembled in mitochondria. Furthermore, serum starvation enhanced ATP synthase translocation to plasma membrane, Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, rescued the phenomena. Additionally, image quantification of mitochondria, showing that mitochondrial fission preference cells expressed more eATP synthase. Therefore, we proposed that eATP synthase trafficking may be related to mitochondrial dynamics. Additionally, ICC and flow cytometry revealed the expression of a critical transcription factor associated with high-risk neuroblastoma, MYCN, correlated with eATP synthase expression. To better understand whether MYCN mediated mitochondrial fission and affected ATP synthase trafficking, we first analyzed MYCN ChIP-sequencing data and found Drp1, Mfns and Parkin possessed the consensus DNA-binding motif of MYCN. Further high-resolution image analysis showed higher mitochondrial fission and eATP synthase expression in MYCN-amplified neuroblastoma. Last, silencing MYCN reduced the fission level by detecting DRP1. In summary, we suggest that trafficking of ectopic ATP synthase may via mitochondrial dynamics.
2023-05-10 | PXD007036 | Pride
Project description:Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.
2020-08-28 | GSE156982 | GEO
Project description:Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defense and enhance viral fitness remain unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprograms mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP-loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signaling protein (MAVS) aggregation and impairs interferon responses. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signaling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly, and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy
2025-04-10 | GSE292579 | GEO