Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging

Abstract

Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.

Redox signalling and ageing: insights from Drosophila

“…The combined (but not individual) knockdown of dPrx3 and dPrx5 led to a strong decrease in the GSH/GSSG ratio and in reduced protein thiol levels, resulting in pro-apoptotic changes and dramatically shortened lifespan [42]. Furthermore, overexpression of dPrx5 targeted to mitochondria, but not to the cytosol or nucleus, partially rescued the shortened survival of dPrx3 and dPrx5 double knock-down mutants under both stressed and control conditions [43]. The authors implicate chronic activation of immune responses, highlighting an important role for mitochondrial redox regulation in this process [43].…”

“…Furthermore, overexpression of dPrx5 targeted to mitochondria, but not to the cytosol or nucleus, partially rescued the shortened survival of dPrx3 and dPrx5 double knock-down mutants under both stressed and control conditions [43]. The authors implicate chronic activation of immune responses, highlighting an important role for mitochondrial redox regulation in this process [43].…”

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

“…Global overexpression increased lifespan by more than 30% [162]. Overexpression of dPrx5 specifically in mitochondria also extended lifespan [163]. dPrx3 is exclusively expressed in mitochondria.…”

The interplay between immunity and aging in Drosophila

“…shows that preventing morphological changes in the mitochondria by overexpression of Dynamin-related protein 1 ( Drp1 ) improves mitochondrial respiratory function and increases lifespan 51 , but the authors did not assess immune transcription. Interestingly, mutants of mitochondrial peroxiredoxins ( dPrx3 and dPrx5 ), involved in the regulation of ROS levels, exhibit increased activation of the immune response, whereas overexpression of these peroxiredoxins extends lifespan and delays the age-related inflammatory response 52 .…”