CAMK1D activates PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA1277120 | ENA |
REPOSITORIES: ENA
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Project description:Although AR-targeted therapies (e.g., enzalutamide) initially improve outcomes of prostate cancer (PCa) patients, resistance inevitably develops, driven in part by prostate cancer stem-like cells (PCSCs). However, the molecular mechanisms linking PCSCs maintenance to enzalutamide resistance (ENZR) remain incompletely characterized. The emergence and reversal of ENZR represent critical clinical challenges in PCa therapeutics. Cancer stem-like cells (CSCs) have been implicated in contributing to ENZR through multiple pathways. Here, we demonstrated that CAMK1D, a Ca²⁺/calmodulin-dependent kinase, is consistently upregulated in PCa with ENZR and contributes to resistance by enhancing mitophagy in PCa cells both in vitro and in vivo. Mechanistically, CAMK1D promotes the expansion of PCSCs by enhancing mitophagy through activation of the AMPK-PINK1 signaling pathway, thereby facilitating cellular adaptation. We reveal that CAMK1D interacts with AMPK, triggering lysosomal AMPK activation via metabolic stress–induced PINK1 phosphorylation. This AMPK-PINK1 cascade reprogramsmitochondrial metabolism to fuel PCSCs expansion. In patient-derived xenograft chimeras, targeting mitophagy or CAMK1D-AMPK signaling pathway suppresses tumor growth and depletes the PCSCs population. Our findings establish mitochondrial hemostasis as an important nexus between ENZR and AMPK-mediated PCSCs enrichment in PCa. CAMK1D emerges as a key regulator of ENZR by orchestrating mitophagy-dependent stemness maintenance. Therapeutically, we developed an Enz-siCAM/HNA nanoformulation that potently reverses ENZR and improves treatment responses.
2025-06-30 | GSE299843 | 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:PTEN-induced kinase 1 (PINK1) is a very short-lived protein that is required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated with and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane protein Synaptojanin 2 Binding Protein (SYNJ2BP) and Synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for activation of mitophagy.
2022-01-14 | GSE193443 | GEO
Project description:The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support recruitment of mitophagy receptors. The ubiquitin ligase substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed a role for FBXO7 in promoting Parkin-dependent mitophagy. Here, we systematically examine the involvement of FBXO7 in depolarization and mtUPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems. We find that FBXO7-/- cells have no demonstrable defect in: 1) kinetics of pUb accumulation, 2) pUb puncta on mitochondria by super-resolution imaging, 3) recruitment of Parkin and autophagy machinery to damaged mitochondria, 4) mitophagic flux, and 5) mitochondrial clearance as quantified by global proteomics. Moreover, global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian-pyramidal syndrome.
2023-06-19 | PXD037797 | Pride
Project description:ATR licenses PINK1-mediated mitophagy
| PRJNA1023223 | ENA
Project description:Dysregulated inflammation is a key driver of disease following infection with the globally important human pathogens, Zika virus (ZIKV) and dengue virus. However, specific mechanisms of inflammation are not well defined. Here, we demonstrate that ZIKV antagonizes mitophagy, or the process of selective degradation of damaged mitochondria. The mechanism of antagonism was through interactions between NS5 and the host protein Ajuba to prevent Ajuba translocation to depolarized mitochondria. We further identify a role of Ajuba in mitophagy through augmenting PINK1 kinase activity. Mitophagy suppression in infected Ajuba-/- cells amplified the cellular integrated stress response (ISR) to promote ZIKV replication, and increased pro-inflammatory cytokine expression dependent on the ISR kinase, PKR. Thus, ZIKV suppresses mitophagy to favor replication and this failure of mitochondrial quality control is translated to inflammation by PKR, suggesting new therapeutic targets to treat flavivirus disease.
2021-09-08 | GSE162688 | 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:PINK1/parkin-dependent mitophagy initially involves (phospho) ubiquitin-proteasome-dependent degradation of certain outer mitochondrial membrane (OMM) proteins (e.g. mitofusins) and then the recruitment of autophagy effectors to more stable ubiquitinated OMM proteins. It is widely assumed that such ubiquitinated mitochondria are ultimately degraded via wholesale mitophagy. However, we demonstrate that mitochondrial degradation occurs via step-wise delivery of separate mitochondrial sub-compartments to lysosomes. OMM and inner mitochondrial material appears to become separately isolated for autophagolysosomal degradation, not only in parkin-overexpressing HeLa cells but also in cells that express endogenous parkin (human embryonic kidney cells and neural progenitor cells) with slower mitophagy kinetics. The remaining inner mitochondrial material becomes degraded only after much prolonged membrane depolarization, involving another proteasome-sensitive step. These combined microscopy and proteomics analyses lend support to the idea that cell stress-induced parkin-dependent mitophagy is a complex regulated multi-step process with distinct sub-compartments separately targeted to autophagic degradation.
2025-05-26 | PXD034136 | Pride
Project description:Cardiomyocytes rely on mitochondrial fatty acid β-oxidation (FAO) for ATP production in the healthy heart but can exhibit marked metabolic flexibility in response to diverse physiological circumstances. Mutations or deficiencies in FAO enzymes can lead to a spectrum of symptoms, ranging from muscle weakness to severe cardiomyopathy, and, in some instances, culminate in neonatal/infantile mortality. It is generally believed that under FAO deficit, mitochondria encounter stress, potentially triggering the initiation of mitophagy, a process crucial for maintaining mitochondrial quality. We explored the link between FAO deficiency and mitophagy utilizing FAO-deficient mice generated through cardiomyocyte-specific deletion of the Carnitine Palmitoyltransferase 2 (CPT2). Intriguingly, our findings contradicted the prevailing hypothesis, revealing an unexpected decline in mitophagy in FAO-deficient hearts. Employing an integrated approach involving quantitative proteomics, metabolomics, and transcriptomics assays, we identified suppressed a PINK1/Parkin signaling pathway in CPT2-deficient heart tissues. Our study demonstrated that the loss of cardiac FAO impairs the PINK1 pathway by modulating the mitochondrial rhomboid protease PARL (presenilin-associated rhomboid-like protein). Furthermore, inhibiting USP30, a mitochondrial deubiquitinating enzyme antagonizing PINK1/Parkin function, restored cardiac mitophagy, thereby alleviating FAO-associated cardiac dysfunction. Notably, the deletion of USP30 conferred a significant survival advantage to FAO-deficient animals, doubling the median survival and substantially improving the maximum survival rate. The study unveiled a novel connection between FAO and PINK1-dependent mitophagy, presenting a potential therapeutic avenue for addressing FAO-deficient cardiomyopathies.
2025-05-02 | GSE266487 | GEO