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Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging

Author

Listed:
  • Juan Ignacio Jiménez-Loygorri

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC)

  • Beatriz Villarejo-Zori

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC)

  • Álvaro Viedma-Poyatos

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC)

  • Juan Zapata-Muñoz

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC)

  • Rocío Benítez-Fernández

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC
    University of Fribourg)

  • María Dolores Frutos-Lisón

    (Food & Health Lab, Research Group on Quality, Safety, and Bioactivity of Plant Foods, CEBAS-CSIC)

  • Francisco A. Tomás-Barberán

    (Food & Health Lab, Research Group on Quality, Safety, and Bioactivity of Plant Foods, CEBAS-CSIC)

  • Juan Carlos Espín

    (Food & Health Lab, Research Group on Quality, Safety, and Bioactivity of Plant Foods, CEBAS-CSIC)

  • Estela Area-Gómez

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC)

  • Aurora Gomez-Duran

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC
    Universidade de Santiago de Compostela)

  • Patricia Boya

    (Centro de Investigaciones Biológicas Margarita Salas, CSIC
    University of Fribourg)

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.

Suggested Citation

  • Juan Ignacio Jiménez-Loygorri & Beatriz Villarejo-Zori & Álvaro Viedma-Poyatos & Juan Zapata-Muñoz & Rocío Benítez-Fernández & María Dolores Frutos-Lisón & Francisco A. Tomás-Barberán & Juan Carlos Es, 2024. "Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45044-1
    DOI: 10.1038/s41467-024-45044-1
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    1. David E. Harrison & Randy Strong & Zelton Dave Sharp & James F. Nelson & Clinton M. Astle & Kevin Flurkey & Nancy L. Nadon & J. Erby Wilkinson & Krystyna Frenkel & Christy S. Carter & Marco Pahor & Ma, 2009. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice," Nature, Nature, vol. 460(7253), pages 392-395, July.
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