Urolithin Α modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and model organism (C. elegans) laboratory research without human clinical data.
PubMed 40944367 · doi:10.1080/15548627.2025.2561073
What was done
Investigated how Urolithin A (UA) regulates inter-organellar communication (endoplasmic reticulum, mitochondria, and lysosomes) and mitophagy during aging. The authors utilized multi-omic profiling, *Caenorhabditis elegans* longevity and muscle function assays, and cultured mammalian cells subjected to stress-induced senescence. Mechanisms involving calcium signaling, DRP-1-mediated mitochondrial fission, and UNC-43/CAMK2D and SKN-1/Nrf2 biogenesis pathways were tested using genetic perturbations and calcium chelation.
What was found
The abstract reports directional findings without numerical values, effect sizes, or confidence intervals. In *C. elegans*, UA stimulated ER calcium release, enhanced lysosomal activity, drove DRP-1-dependent mitochondrial fission, and promoted mitophagy. Chelation of calcium completely blocked UA-induced mitophagy, muscle function improvements, and lifespan extension. UA also stimulated mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/Nrf2 pathways. In cultured mammalian cells, UA increased intracellular calcium, elevated mitochondrial metabolism, and mitigated stress-induced cellular senescence in a calcium-dependent manner.
Why it matters
This study defines a conserved mechanism showing that urolithin A requires calcium signaling to synchronize ER, lysosome, and mitochondrial dynamics to clear damaged mitochondria. It clarifies the intracellular organellar crosstalk driving urolithin A's geroprotective effects in model systems.
Limits
The study is restricted to cell culture models and an invertebrate organism (*C. elegans*); findings cannot be directly extrapolated to human healthspan or disease. The abstract provides no specific sample sizes, statistical variance, or exact quantitative effect sizes. In vivo mammalian lifespan and functional outcomes were not evaluated.
Cited by
- supports Studies in cultured cells and animal models show that urolithin A improves mitochondrial quality.