Mitochondria-Targeted Biomaterials-Regulating Macrophage Polarization Opens New Perspectives for Disease Treatment

International Journal of Nanomedicine, Journal Year: 2025, Volume and Issue: Volume 20, P. 1509 - 1528

Published: Feb. 1, 2025

Abstract: Macrophage immunotherapy is an emerging therapeutic approach designed for modulating the immune response to alleviate disease symptoms. The balance between pro-inflammatory and anti-inflammatory macrophages plays a pivotal role in progression of inflammatory diseases. Mitochondria, often referred as "power plants" cell, are essential organelles responsible critical functions such energy metabolism, material synthesis, signal transduction. functional state mitochondria closely linked macrophage polarization, prompting interest strategies that target regulate this process. To end, biomaterials with excellent targeting capabilities effective properties have been developed influence mitochondrial function polarization. However, comprehensive summary biomaterial-driven modulation control phenotypes still lacking. This review highlights polarization discusses mediated by biomaterials, including mitochondria-targeted biomaterials. Finally, prospects challenges use these explored, emphasizing their potential be translated clinic. It anticipated will serve valuable resource materials scientists clinicians development next-generation Keywords: macrophages,

Language: Английский

---

A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy

Cell Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 11, 2025

Abstract PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, process termed mitophagy. Previous studies on PINK1 mainly focused its post-translational modifications, while transcriptional regulation much less understood. Herein, we reported novel mechanism control transcription by SMAD Family Member 3 (SMAD3), an essential component transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, observed that mitochondrial depolarization promotes transcription, and SMAD3 likely to be nuclear mediating transcription. Intriguingly, positively transactivates independent canonical TGFβ components, such as TGFβ-R1, SMAD2 or SMAD4. Second, found activates PINK1-mediated phosphorylation at serine 423/425. Therefore, constitute positive feedforward loop Finally, activation provides important pro-survival signal, depletion sensitizes cells cell death caused stress. In summary, our findings identify non-canonical function mitophagy feedback activation. Understanding this regulatory deeper insight into pathological pathogenesis neurodegenerative diseases Parkinson's disease.

Language: Английский

---

Quality control of mitochondrial nucleoids

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

---

Parkinson’s Disease: The Neurodegenerative Enigma Under the “Undercurrent” of Endoplasmic Reticulum Stress

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3367 - 3367

Published: April 3, 2025

Parkinson's disease (PD), a prevalent neurodegenerative disorder, demonstrates the critical involvement of endoplasmic reticulum stress (ERS) in its pathogenesis. This review comprehensively examines role and molecular mechanisms ERS PD. represents cellular response triggered by imbalances (ER) homeostasis, induced factors such as hypoxia misfolded protein aggregation, which activate unfolded (UPR) through inositol-requiring enzyme 1 (IRE1), kinase R-like (PERK), activating transcription factor 6 (ATF6) pathways. Clinical, animal model, studies have consistently demonstrated strong association between PD ERS. Abnormal expression ERS-related molecules patients' brains cerebrospinal fluid (CSF) correlates with progression. In models (e.g., Drosophila mice), inhibition alleviates dopaminergic neuronal damage. Cellular experiments reveal that PD-mimicking pathological conditions induce ERS, while interactions mitochondrial dysfunction promote apoptosis. Mechanistically, (1) aggregation α-synuclein (α-syn) mutually reinforce neuron damage; (2) leucine-rich repeat 2 (LRRK2) gene mutations thrombospondin-1 (THBS1)/transforming growth beta (TGF-β1) interactions; (3) Parkin PTEN-induced (PINK1) regulate Furthermore, interacts dysfunction, oxidative stress, neuroinflammation to exacerbate injury. Emerging therapeutic strategies show significant potential, including artificial intelligence (AI)-assisted drug design targeting pathways precision medicine approaches exploring non-pharmacological interventions personalized electroacupuncture. Future research should focus on elucidating identifying novel targets develop more effective treatments for patients, ultimately improving their quality life.

Language: Английский

---

Chuangxiong-Danggui Herb Pair Alleviated Cognitive Deficits of App/Ps1 Mice by Promoting Fundc1-Mediated Mitophagy

Published: Jan. 1, 2025

Background: Disruption of receptor-mediated mitophagy contributes to neuronal damage in AD. Chuangxiong-Danggui herb pair (CDHP) is classic herbal applied treating neurodegenerative diseases like AD, ALS, PD. Studies have indicated the neuroprotective effects CDHP, underlying mechanisms by which CDHP attenuates impairment AD remains be elucidated.PurposeThe objective this work was investigate anti-AD mechanism APP/PS1 mice mainly based on FUNDC1-mediated mitophagy.MethodsBehavioral assessments were conducted C57BL/6J and following treatment, alongside an evaluation morphology hippocampal region. In vitro, HT-22 cells induced Aβ25-35 before treated with CDHP. The investigated using transmission electron microscopy, Golgi staining, immunofluorescence, siRNA, Western blot analysis.ResultsResults from passive avoidance test MWM that significantly mitigated cognitive deficits mice, accompanied a reduction pathological CA1 CA3 regions hippocampus. Further testing found significant dendritic spines density rescued protein synaptophysin PSD-95 elevated group, while Aβ plaques deposition reduced. Simultaneously, markedly inhibits apoptosis decreased levels Cleaved Caspase-12 enhanced expression Bcl-2/Bax both vivo vitro. Additionally, improved mitochondrial function model decreasing abnormal mitochondria increasing COXIV. TEM results revealed clear mitophagy-autophagosomes nearly absent p62 LC3B treatment. Furthermore, increased FUNDC1 transgenic or AD-like cell model, luckily, it restoring II/I ratio vitro.ConclusionThe findings suggest dysfunction enhancing reduced injury.

Language: Английский

---

A novel dual CCK/ GLP-1 receptor agonist ameliorates cognitive impairment in 5 × FAD mice by modulating mitophagy via the PINK1/Parkin pathway

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 154, P. 114612 - 114612

Published: April 6, 2025

Language: Английский

---

USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: May 2, 2025

Abstract Background Mitophagy, essential for cellular homeostasis, is involved in eliminating damaged mitochondria and associated with cancer progression chemoresistance. The specific impact of mitophagy on microsatellite instability-high (MSI-H) colorectal (CRC) still under investigation. Ubiquitination, a post-translational modification, controlling protein stability, localization, function. This study identifies USP14, deubiquitinating enzyme, as key regulator MSI-H CRC. Methods A enzyme (DUBs) siRNA library screening identified USP14 mitophagy. Tissue samples from patients were analyzed using immunohistochemistry Western blot. knockdown cell lines generated lentiviral transfection. Protein interactions between BAG4 confirmed by co-immunoprecipitation, while quantitative PCR was used to measure gene expression. Mitochondrial proteins extracted analyze mitophagy, flow cytometry assess apoptosis. Finally, mouse xenograft model employed USP14’s role tumor growth oxaliplatin sensitivity. Results Screening reveals that inhibits CRC show high expression which correlates poor prognosis. Functional analyses reveal knocking down reduces growth, increases sensitivity oxaliplatin. Mechanically, K48-deubiquitinating stabilizing at K403, prevents the recruitment Parkin mitochondria. significant clinical relevance BAG4, PRKN are proved tissues. Conclusions highlights USP14/BAG4/PRKN axis critical pathway (MSI-H), suggesting targeting could inhibit improve chemotherapeutic outcomes. These findings underscore importance ubiquitination biology, indicating potential therapeutic target

Language: Английский

---

Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119988 - 119988

Published: May 1, 2025

Language: Английский

---

Presynapses are mitophagy pit stops that prevent axon degeneration

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 9, 2024

Abstract Defects in neuronal mitophagy have been linked to neurodegenerative diseases including Parkinson’s disease. However, despite the importance of homeostasis, mechanistic basis for neurodegeneration when is defective unclear. Here, using human neurons, we discover that presynapses are pit stops damaged axonal mitochondria. We show while mitochondrial damage and PINK1/Parkin activation events distributed throughout axons, initiation autophagosome formation restricted presynapses, which contain machineries required mitophagy. Being primary sites mitophagy, were vulnerable was defective. observed local cytochrome c release within from an accumulation This resulted downstream degradative caspase activation, defining a mechanism neurodegeneration. Pharmacological rescue axon degeneration achieved through synthetic upregulation receptor mediated with clinically approved compound Roxadustat, revealing potential therapeutic avenue

Language: Английский

---

Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(14), P. 5793 - 5811

Published: Oct. 28, 2024

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries involves various complex pathological mechanisms factors. Previous studies have demonstrated close association between atherosclerosis inflammatory damage, metabolic disorders, gut microbiota. It also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, biogenesis. Mitophagy has been recognized previously unexplored mechanism contributing injury in atherosclerosis. Our study aims further elucidate the potential relationship AS-induced mitophagy dysfunction interaction of TMBIM6 NDUFS4. Data from that AS mice was associated with substantial activation oxidative stress along marked reduction expression increased fission, leading homeostasis disruption. However, under pharmacological intervention, levels significantly increased, fission notably reduced, damage were suppressed, while necroptotic pathways cells blocked. Interestingly, deletion or NDUFS4 animal models lines markedly impaired therapeutic effects drug, disrupting its regulation re-emergence responses damage. Metabolomics analysis revealed autophagy plays pivotal regulatory role during drug intervention after genetic modification The (macroautophagy/mitophagy) alleviated negative induced by lipid cells, likely TMBIM6-NDUFS4 axis. Subsequent gene experiments knocking out negates on lipid-induced function. In summary, our research reveals phenotypic through influenced Pharmacological can restore regulating via pathway. This novel insight suggests may serve key target for

Language: Английский

---