Abstract

In the nervous system, mitochondrial dysfunction affects neuronal longevity and their ability to respond to different forms of stress. Substantial evidence points to the mitochondria as the central executor of neurodegenerative processes. This degenerative process resembles the events that result in degeneration of the axon distal to an injury, which are known as Wallerian Degeneration (WD). WD is an evolutionarily conserved and not completely understood mechanism where different forms of mitochondrial dysfunction like ATP depletion, strong Ca+2 influxes and redox changes cause loss of the homeostasis in the protein folding environment of this organelle. In order to recover homeostasis, cells activate a signaling pathway known as mitochondrial unfolded protein response (UPRMT). Only three components of the mitochondrial UPR have been identified as nuclear regulators of the pathway: defective ventriculus (DVE), Ubiquitin like protein (UBL) and Cryptochephal (Crc). Nevertheless, UPRMT is emerging as an important adaptive stress response pathway that ensures the optimal function and quality of the mitochondria acting as a surveillance pathway that responds to the changes in homeostasis. Little is known about how the UPRMT¬¬ is regulated during aging in Drosophila and its involvement in neurodegeneration. In this work, we evaluated the effect of genes associated to the UPRMT in neuronal integrity during aging. To fulfill this propose, we designed, created and validated a novel genetic tool for the study of UPRMT activation in Drosophila. Downregulation of the gene encoding UPRMT activator DVE led to a decrease in lifespan with locomotor defects, affecting neuronal integrity in aging, but not in young flies. This was correlated with impaired mitochondrial morphology. Importantly, flies bearing the knockdown of DVE could not activate the UPRMT indicated with the novel UPRMT fluorescent sensor. Counterintuitively, overactivation of the UPRMT by the overexpression of DVE was no viable and led to neuronal death, phenotype that was rescued through apoptosis inhibition. Notably, the UPRMT fluorescent sensor showed a dysregulation of the pathway in Drosophila Parkinson’s disease models. This work gives insights of the cryptic pathway of the UPRMT and how its overactivation would affect already damaged neurons.