Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
Juan Ignacio Jiménez-LoygorriBeatriz Villarejo-ZoriÁlvaro Viedma-PoyatosJuan Zapata-MuñozRocío Benítez-FernándezMaría Dolores Frutos-LisónFrancisco Abraham Tomás-BarberánJuan Carlos EspínEstela Area-GómezAurora Gomez-DuranPatricia BoyaPublished in: Nature communications (2024)
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.
Keyphrases
- nlrp inflammasome
- high fat diet induced
- oxidative stress
- cell death
- endothelial cells
- copy number
- dendritic cells
- gene expression
- crispr cas
- insulin resistance
- metabolic syndrome
- adipose tissue
- signaling pathway
- brain injury
- dna methylation
- wild type
- diabetic retinopathy
- immune response
- reactive oxygen species
- long non coding rna