Nature Communications · 11 authors, 5 centres
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Using mito-QC reporter mice across multiple organs, the authors found that mitophagy is increased or unchanged in old versus young mice, while cytosolic mtDNA and cGAS/STING inflammatory signaling are elevated with age. Pharmacological induction of mitophagy with urolithin A in old mice attenuates cGAS/STING activation and ameliorates neurological decline.
Mitophagy was significantly higher in kidney, brain, retinal pigment epithelium, neuroretina, cerebellum, and liver of old mice, while unchanged in pancreas, spleen, muscle, heart, and lungs, driven by the PINK1/Parkin pathway. Old mice showed increased cytosolic mtDNA and activation of the cGAS/STING/type I interferon inflammatory axis. Transcriptomic analysis revealed marked upregulation of the type I interferon response in the retina of old mice. These alterations were replicated in primary human fibroblasts from elderly donors. Pharmacological induction of mitophagy with urolithin A in old mice attenuated cGAS/STING activation and ameliorated neurological functional decline.
