Gut-brain axis neurodegeneration in a Drosophila model of Parkinson’s disease is linked to mitochondrial dysfunction

Abstract The innate immune response mounts a defence against foreign invaders, but the inappropriate induction of an innate immune response can cause diseases. Previous studies have provided ample evidence showing that mitochondria can be repurposed to promote inflammatory signalling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1 cause early-onset Parkinson’s disease (PD), and studies using Drosophila melanogaster have shown that pink1 mutants accumulate damaged mitochondria. Here, we showed that defective mitochondria in pink1 mutants activate Relish targets and demonstrated that inflammatory signalling causes intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells and metabolic reprogramming, which leads to neurotoxicity. We found that Relish signalling is activated downstream of a pathway stimulated by cytosolic DNA. The suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and protects neurons in the brain. We thus conclude that the gut-brain axis causes neurotoxicity in a fly model of PD through a mechanism involving mitochondrial dysfunction.