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- Title
Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
- Authors
Jiménez-Loygorri, Juan Ignacio; Villarejo-Zori, Beatriz; Viedma-Poyatos, Álvaro; Zapata-Muñoz, Juan; Benítez-Fernández, Rocío; Frutos-Lisón, María Dolores; Tomás-Barberán, Francisco A.; Espín, Juan Carlos; Area-Gómez, Estela; Gomez-Duran, Aurora; Boya, Patricia
- Abstract
Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan. Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.
- Subjects
TYPE I interferons; INTERFERON receptors; CLINICAL deterioration; INFLAMMATION; AUTOPHAGY
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45044-1