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Updated: Jul 10, 2026
Single Drosophila Ommatidium Dissection and Imaging
Published on: August 19, 2011
Cytosolic mtDNA and associated EYA-mediated pro-inflammatory signaling modulate healthspan in Drosophila
David Walker1, Ricardo Aparicio1, Roberta Alessi2
1University of California, Los Angeles.
Abstract:
Mitochondrial dysfunction and pro-inflammatory signaling are each key drivers of aging. However, a clear understanding of the connections between mitochondrial homeostasis, inflammation and lifespan determination remains elusive. Upon mitochondrial stress or damage, mtDNA can be released into the cytosol thus encountering cytosolic DNA sensors and activating pro-inflammatory responses. Here, we report a striking age-related increase in cytosolic mtDNA, which can be counteracted by mitophagy, in Drosophila brain and muscle tissue. We find that upregulation of DNase II, an acid DNase which digests DNA in the autophagy-lysosome system, reduces cytosolic mtDNA levels in aged flies and prolongs healthspan. Reducing the abundance of cytosolic DNA in aged flies also dampens Rel/NF-κB pro-inflammatory signaling. Furthermore, we show that inhibition of EYA, a Rel/NF-κB-binding protein involved in immune sensing of DNA, in aging neurons counteracts brain aging and prolongs healthspan. Our findings identify DNase II and EYA as therapeutic targets to prolong healthspan.
Insights
Aging increases mitochondrial DNA in the cytosol, triggering inflammation. Enhancing DNase II or inhibiting EYA in flies reduces this DNA, dampens inflammation, and extends healthspan, revealing new therapeutic targets.
Area of Science:
- Cellular Biology
- Aging Research
- Immunology
Background:
- Mitochondrial dysfunction and inflammation are key aging drivers.
- Cytosolic mitochondrial DNA (mtDNA) release activates inflammatory responses.
- The link between mitochondrial homeostasis, inflammation, and lifespan is not fully understood.
Purpose of the Study:
- To investigate the role of cytosolic mtDNA in aging.
- To identify therapeutic targets for extending healthspan.
Main Methods:
- Studied age-related changes in cytosolic mtDNA in Drosophila.
- Assessed the effects of mitophagy, DNase II upregulation, and EYA inhibition on aging phenotypes.
- Measured inflammatory signaling pathways, including Rel/NF-κB.
Main Results:
- Cytosolic mtDNA increases with age in Drosophila tissues and can be reduced by mitophagy.
- Upregulating DNase II decreases cytosolic mtDNA, dampens Rel/NF-κB signaling, and prolongs healthspan.
- Inhibiting EYA in aging neurons counteracts brain aging and extends healthspan.
Conclusions:
- Cytosolic mtDNA accumulation contributes to age-related inflammation and reduced healthspan.
- DNase II and EYA are identified as potential therapeutic targets to combat aging and extend healthspan.
