PXD056571-1

PXD056571 is an original dataset announced via ProteomeXchange.

Title	Urolithin A rewires inter-organellar communication via calcium signaling to promote mitophagy and longevity
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-10-15
AnnouncementXML	Submission_2025-10-15_09:16:34.028.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martina Samiotaki
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: NEWT:6239;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-07 23:12:19	ID requested
⏵ 1	2025-10-15 09:16:34	announced

10.1080/15548627.2025.2561073;

submitter keyword: ITR-1/InsP3R, mitophagy, lysosome, TMCO-1/TMCO, MCU-1/MCU1, geroprotection, calcium, mitochondria, EMC-3/EMC3,aging, urolithin A, ER

Konstantinos Palikaras
contact affiliation	Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Athens, Greece
contact email	palikarask@med.uoa.gr
lab head
Martina Samiotaki
contact affiliation	Protein Analysis Laboratory B.S.R.C. "Alexander Fleming", Alexander Fleming Street 34 16672, Vari, Greece
contact email	samiotaki@fleming.gr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056571
     1. Label: PRIDE project
     2. Name: Urolithin A rewires inter-organellar communication via calcium signaling to promote mitophagy and longevity