# Cytosolic mtDNA and associated EYA-mediated pro-inflammatory signaling modulate healthspan in Drosophila

## TL;DR

This study shows that reducing cytosolic mitochondrial DNA and related inflammation can extend healthspan in aging fruit flies.

## Contribution

The novel finding is that DNase II and EYA are key regulators of healthspan through mtDNA and inflammation control in Drosophila.

## Key findings

- Cytosolic mtDNA increases with age in Drosophila brain and muscle, but can be reduced by mitophagy.
- Upregulating DNase II lowers cytosolic mtDNA and extends healthspan in aged flies.
- Reducing cytosolic DNA dampens pro-inflammatory signaling and inhibiting EYA in neurons prolongs healthspan.

## 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.