Unveiling the role of mitophagy induction as a strategy to reduce age-associated inflammation

A study published in the journal Nature Communications by the Autophagy Laboratory of the Margarita Salas Center for Biological Research (CSIC) shows that mitophagy is specifically stimulated during aging, although autophagy in general decreases, to avoid having mitochondrial DNA in the cytosol and prevent the activation of the inflammatory response.

During aging autophagy, the main intracellular recycling system, decreases, causing waste accumulation within our cells. This is especially pronounced in post-mitotic tissues such as neurons, which cannot partition and dilute these wastes among their daughter cells. Autophagy dysfunction has been included among the key hallmarks of aging, which also include mitochondrial dysfunction and chronic inflammation.

Previous work by the CIB Margarita Salas’ research group, led until 2022 by lead author Patricia Boya, demonstrated that, although overall autophagy declines with age, cells activate other more selective recycling mechanisms such as chaperone-mediated autophagy (CMA).

The study now published in Nature Comm. examines whether mitophagy, the specific recycling of mitochondria through autophagy, decreases or increases with age. For this purpose, young (6-8 months) and old (22-26 months) mice expressing a fluorescent reporter system were used to obtain an atlas of mitophagy during aging, showing that it remains stable or increases in all the organs analyzed. In addition, transcriptomic analysis and molecular studies allowed us to demonstrate a simultaneous activation of the immune response to cytosolic DNA mediated by the cGAS/STING axis, and to characterize it as DNA of mitochondrial origin (mtDNA).

Based on these results, Jiménez-Loygorri et al. conclude that the increase of mitophagy with age may be a response of cells to try to reduce the outflow of mtDNA from damaged mitochondria to the cytosol, as well as the consequent inflammation. To confirm this, aged mice were treated with a mitophagy inducer called Urolithin A. Those rodents that received the drug showed lower levels of inflammation at the end of treatment and, as a consequence, improved cognitive, visual, and motor function.

The authors replicated these studies in several mouse organs and in primary cultures of aged human donors, showing that this phenomenon is conserved at the systemic level and between species.

The results obtained in this work open the door to the possibility of reducing age-associated neuroinflammation through mitophagy. This strategy has advantages because it does not alter the physiology of the immune system and has no immunosuppressive effect. Preliminary clinical trials with Urolithin A have shown that this molecule can reduce blood markers of inflammation such as C-reactive protein in healthy volunteers.

This study is the result of the collaboration of the Autophagy Laboratory and the group of Estela Area-Gómez, both from CIB Margarita Salas, Aurora Gómez-Durán, from CiMUS, and Juan Carlos Espín, from CEBAS-CSIC.

Reference: Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging. Jiménez-Loygorri, J.I., Villarejo-Zori, B., Viedma-Poyatos, Á. et al. Nat Commun 15, 830 (2024). https://doi.org/10.1038/s41467-024-45044-1