Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE312563 | GEO | 2026/07/06
REPOSITORIES: GEO
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Project description:Acute kidney injury (AKI) is an unsolved global public health problem, requiring new effective therapies. Cytokinesis cycle 42 (CDC42) is a potent therapeutic target for multiple diseases, whereas its function in AKI remains unknown. Here we report that inhibition of CDC42 protects against AKI via orchestrating kruppel-like factor 2 (KLF2)/HIF-1α/PINK1-mediated mitophagy. We showed Cdc42 was not only abundantly expressed in murine renal tubular epithelial cells (RTECs) but also up-regulated in human and murine RTECs post cisplatin exposure, respectively. Then, administration of a CDC42 inhibitor in vivo and in vitro, conditional knockdown of Cdc42 in murine RTECs, and knockout of CDC42 in human RTECs abated cisplatin-caused mitochondrial dysfunction and kidney injury. Furthermore, by integratively using transcriptome sequencing, bioinformatics analysis, dual luciferase reporter assay, and chromatin immunoprecipitation, we found CDC42 inhibition alleviated mitochondrial dysfunction via KLF2/HIF-1α/PINK1-mediated mitophagy, during which CDC42 inhibition enhanced the promoter activity of KLF2, while KLF2 transcriptionally up-regulated HIF-1α, and HIF-1α subsequently transcriptionally up-regulated PINK1, the crucial regulator of mitophagy. Moreover, the function of KLF2 and HIF-1α in CDC42-mediated RTECs damage and mitochondrial dysfunction was verified. In conclusion, we uncovered the role and underlying mechanism of CDC42 in AKI, providing AKI patients with new therapeutic strategies.
2026-03-05 | GSE274116 | GEO
Project description:Global analysis of transcriptional changes in Drosophila park25 (parkin) and pink1 (Pink1) mutants. PARKIN and PINK1 are part of the organellar and molecular mitochondrial quality control and loss-of-function mutations have been identified as familial causes of Parkinson's disease. Young and old flies were used to identify changes in expression patterns during aging. Heads or whole flies were used to identify neuron-specific transcriptional changes that may be relevant to PD.
2017-02-17 | E-MTAB-1406 | biostudies-arrayexpress
Project description:Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson’s disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage by a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the PAM import motor, blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 in TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.
2025-08-06 | GSE298056 | GEO
Project description:Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
2019-06-22 | GSE126910 | GEO
Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
2023-09-24 | GSE243532 | GEO
Project description:The PINK1/Parkin pathway is responsible for targeting damaged mitochondria for degradation via mitophagy. Because genetic evidence links impaired mitophagy to Parkinson’s disease, pharmacologic enhancement of mitophagy represents a promising disease-modifying strategy. Here, we characterize two pharmacological mitophagy activators: a new Parkin activator, FB231, described here and the reported PINK1 activator MTK458. We demonstrate that both compounds activate their targets and lower the threshold for PINK1/Parkin-mediated mitophagy induced by mitochondrial stressors. Using global proteomics, however, we also find that FB231 and MTK458 exert mild mitochondrial stress that leads to cleavage of OPA1 and activation of the integrated stress response, in a PINK1/Parkin-independent manner. Both compounds cause mitochondrial stress and thereby sensitizes cells to mitophagy induction by classical mitochondria toxins. We provide a model that rationalizes this hitherto unknown mechanism for mitophagy activators, whereby normally “silent” mitochondrial toxins can act as potent PINK1/Parkin potentiators in the context of mitochondrial stress.
2025-06-03 | PXD058150 | Pride
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, associated with poor response to therapies and high mortality. We identify that phosphodiesterase 7A (PDE7A) is overexpressed in the majority of TNBC, and a higher level of PDE7A associates with poor prognosis. The PI3K/AKT pathway, via the transcription factor IRF1, stimulates the expression of PDE7A in TNBC cells. PDE7A inhibition attenuates TNBC growth in both cell culture and mouse models of TNBC. Inhibition of PDE7A suppresses de novo pyrimidine biosynthesis, in part through the downregulation of the enzyme dihydroorotate dehydrogenase (DHODH). DHODH suppression attenuates TNBC tumor growth, mirroring the effects of PDE7A inhibition, and ectopic DHODH expression rescues PDE7A-inhibition-induced tumor suppression. Pharmacological co-targeting of PDE7A and DHODH potently inhibits TNBC tumor growth and metastasis. These findings identify the PDE7A→ DHODH→ de novo pyrimidine biosynthesis pathway as a key driver of TNBC, offering additional therapeutic opportunities for TNBC patients.
2025-09-15 | GSE192830 | GEO
Project description:The mitochondrial kinase PINK1 and the cytosolic ubiquitin ligase (E3) Parkin is involved in mitochondrial quality control. PINK1, which phosphorylates ubiquitin at serine 65 residue and the ubiquitin-like (Ubl) domain of Parkin at serine 65 residue, promotes the Parkin activation and translocation to damaged mitochondria. When Parkin is activated, the Ubl domain are ubiquitinated at lysine 27 (K27) and lysine 48 (K48) residues. It remains unclear whether K27/K48 ubiquitination contributes to Parkin activity. In this study, we blocked the ubiquitination of K27 and/or K48 residues to examine the effects of the Parkin Ubl ubiquitination in Drosophila. Parkin replaced K27 with arginine (K27R) rescued the lethality of flies by PINK1 and Parkin co-expression whereas K48 replacement with arginine did not. Parkin K27R exhibited less ability of mitochondrial fragmentation and mitochondrial arrest, which are mediated by the degradation of Parkin E3 substrates Mitofusin and Miro, respectively. The pathogenic K27N Parkin, unlike K27R Parkin, was found to be completely devoid of E3 activity, suggesting not only that K27N Parkin is not ubiquitin-modified at the K27 residue but also that the structure of the Ubl domain itself is largely affected. Ubiquitin attached to the K27 residue of the Ubl domain during PINK1-mediated Parkin activation was likely to be phosphorylated because K27R Parkin showed less ability of Parkin self-association upon the reduction of the mitochondrial membrane potential. Our study suggests a new Parkin activation mechanism where an activating complex for Parkin is formed through phospho-ubiquitin attached to the K27 residue of the Ubl domain.
2022-08-24 | PXD026554 | JPOST Repository
Project description:Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early onset Parkinson disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM) forming a high molecular weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates ubiquitin, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved, remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress, such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 NT-CTE module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.
2024-03-02 | PXD047765 | Pride
Project description:Loss-of-function mutations in the parkin gene can cause early onset Parkinson’s disease, a movement disorder resulting from the selective degeneration of dopaminergic neurons in the basal ganglia. Analogously, movement deficits and loss of a subset of dopaminergic neurons are observed in Drosophila melanogaster homozygous for null mutations in parkin. Parkin is an E3 ubiquitin ligase that functions with the mitochondrial localized serine/threonine kinase PINK1 in a pathway required to maintain mitochondrial integrity. We previously established that the PINK1/Parkin pathway functions in Drosophila dopaminergic and cholinergic neurons to maintain mitochondrial membrane potential. However, the mechanisms through which the PINK/Parkin pathway selectively impacts dopaminergic neuron survival remains unclear, as do the mechanisms that lead to the selective vulnerability of dopaminergic neurons in Parkinson’s disease. Because the transcriptome of a cell determines its identity we hypothesized that knowledge of the transcriptional alterations that occur in dopaminergic neurons isolated from parkin null Drosophila would provide insight into the mystery of selective vulnerability in Parkinson's disease. Results: To test our hypothesis we measured the transcriptome of dopaminergic and cholinergic neurons isolated from isogenic heterozygous and homozygous parkin null mutants using a novel flow cytometry-based method we developed. Computational analysis and experimental confirmation demonstrate that our method allows for the successful expression analysis of defined neural subsets from the Drosophila brain. In addition, our dataset implicates iron handling and dopamine signaling as being significantly dysregulated in parkin null dopaminergic neurons. Conclusions: Our flow cytometry-based method allows for the isolation and microarray analysis of neuronal subsets from the adult Drosophila brain. Our microarray analyses implicate iron handling and dopamine metabolism as contributing factors in the etiology of parkin-associated early onset Parkinson’s disease. Here we provide a novel dataset that may serve as a foundation for subsequent functional analyses of the pathways underlying neuronal selective vulnerability in Parkinson's disease.
2020-08-27 | GSE80277 | GEO