Tier 3 — preclinical

Urolithin A modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing

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
Autophagy 2025 21(12):3097-3122

Bibliography

PubMed
PMID 40944367
PubMed Central
PMC12758194
DOI
10.1080/15548627.2025.2561073

Study snapshot

DesignMechanistic multi-omic study in C. elegans and mammalian cells
ModelC. elegans and mammalian cellular models
SampleMultiple experimental cohorts and cell systems
InterventionUrolithin A exposure with genetic and pharmacologic interrogation of calcium and organelle pathways
DurationVaried by experiment
EndpointsER-to-mitochondria calcium signaling; DRP1-mediated mitochondrial fission; Mitophagy; Lysosomal activity; Mitochondrial biogenesis; Healthspan and lifespan in C. elegans

What the study showed, in plain terms

This 2025 paper adds a mechanistic layer beyond the original 'Urolithin A activates mitophagy' story. It links Urolithin A to ER calcium release, mitochondrial calcium uptake, DRP1-mediated fission, lysosomal activity and Nrf2-related mitochondrial adaptation, connecting mitophagy to broader inter-organelle communication.

Key findings

Urolithin A restored communication among mitochondria, endoplasmic reticulum and lysosomes.

Calcium signaling was required for efficient Urolithin A-induced mitophagy in C. elegans.

The pathway involved DRP1-mediated fission and calcium-dependent Nrf2-related mitochondrial biogenesis.

Mammalian cells showed related calcium, mitophagy and metabolic responses.

What this study can and cannot tell us

Mechanistic preclinical models cannot establish that the same pathway operates at the same magnitude in supplemented humans.

C. elegans longevity findings do not translate directly to human lifespan.

Direct molecular targets in human tissues remain incompletely defined.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology