論文 - 詳細
| RRC ID | 87975 |
|---|---|
| 著者 | Roussos A, Kitopoulou K, Borbolis F, Ploumi C, Gianniou DD, Li Z, He H, Tsakiri E, Borland H, Kostakis IK, Samiotaki M, Trougakos IP, Bohr VA, Palikaras K. |
| タイトル | Urolithin Α modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing. |
| ジャーナル | Autophagy |
| Abstract |
Mitochondrial dysfunction and impaired mitophagy are hallmarks of ageing and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, Urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analysis reveals that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In Caenorhabditis elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.Abbreviations: Ca2+: calcium ions; BJ: human foreskin fibroblasts; BNIP3: BCL2 interacting protein 3; BP: bipyridyl; CAMK2D: calcium/calmodulin dependent protein kinase II delta; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DEGs: differentially expressed genes; DEPs : differentially expressed peptides; DFP: deferiprone; DNM1L/DRP1: dynamin 1 like; EGTA: ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; EMC: endoplasmic reticulum membrane protein complex; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone; GO: gene ontology; GSVA: Gene Set Variation Analysis; HUVECs: human umbilical vein endothelial cells; IMM: inner mitochondrial membrane; ITPR/InsP3R: inositol 1,4,5-triphosphate receptor; MAM: mitochondria-associated ER membrane; MAPK: mitogen-activated protein kinase; MCU: mitochondrial calcium uniporter; MEFs: mouse embryonic fibroblasts; NAC : N-acetylcysteine; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; OMM: outer mitochondrial membrane; PCA: principal-component analysis; PPARGC1A/PGC1α: PPARG coactivator 1 alpha; PQ: paraquat; TMCO: transmembrane and coiled-coil domains 1; TMRE: tetramethylrhodamine ethyl ester perchlorate; UA: urolithin A; VDAC: voltage dependent anion channel. |
| 巻・号 | 21(12) |
| ページ | 3097-3122 |
| 公開日 | 2025-12-1 |
| DOI | 10.1080/15548627.2025.2561073 |
| PMID | 40944367 |
| PMC | PMC12758194 |
| MeSH | Aging* / drug effects Aging* / metabolism Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / metabolism Calcium* / metabolism Calcium Signaling / drug effects Coumarins* / pharmacology Endoplasmic Reticulum / drug effects Endoplasmic Reticulum / metabolism Humans Lysosomes / drug effects Lysosomes / metabolism Mitochondria / drug effects Mitochondria / metabolism Mitochondrial Dynamics / drug effects Mitophagy* / drug effects |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 5.1 |
| リソース情報 | |
| 線虫 | tm1108 tm1605 |