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Urolithin A rewires inter-organellar communication via calcium signaling to promote mitophagy and longevity

ABSTRACT: Mitochondrial damage and mitophagy deregulation are hallmark features of aging and age-related pathologies. Urolithin A (UA), a potent mitophagy inducer, is known to confer neuroprotection, maintain muscle integrity, and extend healthspan and lifespan across diverse species. However, the molecular mechanisms underlying UA-mediated mitophagy remain largely unknown. Here, we demonstrate that UA treatment modulates cytosolic calcium levels, which are essential for initiating robust mitophagy in both neurons and muscles. Transcriptomic and proteomic analyses reveal that UA facilitates the reorganization of interorganellar communication between the endoplasmic reticulum (ER), lysosomes, and mitochondria, a process that is highly dependent on calcium signaling. Our findings suggest that calcium is released from the ER, subsequently enhancing lysosomal activity and facilitating mitochondrial entry, ultimately leading to mitochondrial fission and the successful execution of mitophagy. Notably, calcium chelation abolishes UA-induced mitophagy, leading to impaired muscle function and diminished lifespan extension, underscoring the indispensable role of calcium dynamics.We further found that UA-induced calcium elevation triggers mitochondrial biogenesis through the activation of UNC-43/CaMKII and SKN-1/Nrf2, mechanisms critical for healthspan and lifespan extension. In human cells, UA supplementation not only induces mitophagy but also enhances mitochondrial metabolism and prevents stress-induced senescence in a calcium-dependent manner. Ultimately, our findings uncover the mechanistic insights of UA-mediated geroprotection and underscore the central role of calcium dynamics in orchestrating the crosstalk between different cellular compartments, thereby sustaining energy homeostasis and overall organismal physiology.

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ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Martina Samiotaki

LAB HEAD: Konstantinos Palikaras

PROVIDER: PXD056571 | Pride | 2025-10-15

REPOSITORIES: Pride

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Project description:Background Chronic anxiety imposes a major global health burden, yet existing treatments remain inadequate, with limited efficacy or significant side effects. Mitochondrial abnormalities have emerged as key contributors to anxiety-related phenotypes, suggesting that targeting mitochondrial function may offer a novel therapeutic avenue. Urolithin A (UA), a gut microbiota-derived metabolite known to enhance mitochondrial function, has shown neuroprotective effects in preclinical models of aging and neurodegeneration. However, its potential in modulating anxiety and underlying neuronal mechanisms remains unexplored. Methods We examined the effects of UA in two rodent models of heightened anxiety: a natural variation model and a genetically selected high stress-reactivity line. Animals received chronic UA supplementation, and anxiety-like behaviors were assessed across multiple paradigms. Single-nucleus RNA sequencing was performed to identify molecular alterations in nucleus accumbens (NAc) medium spiny neurons (MSNs), incorporating MitoPathway analyses to examine mitochondrion-related transcriptomic signatures. Electrophysiological, immunohistochemical, and morphological analyses were conducted to assess mitochondrial pathways and synaptic function. Results UA selectively reduced anxiety-like behaviors in high-anxiety animals, both males and females, leaving non-anxious controls unaffected. Transcriptomic analyses revealed widespread mitochondrial and synaptic dysregulation in high-anxiety MSNs, with impaired mitophagy emerging as a core feature. UA treatment restored these transcriptomic signatures, normalizing mitophagy-related pathways across all MSN subtypes tightly linked to restored synaptic pathways. These changes translated into structural and functional rescue of MSN dendritic architecture, spine density, and excitatory synaptic transmission. Conclusions These findings identify mitophagy deficits in NAc MSNs as a hallmark of heightened anxiety and highlight UA as a promising mechanism-based intervention.

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Urolithin A rewires inter-organellar communication via calcium signaling to promote mitophagy and longevity

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