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Fig. 1 | Egyptian Journal of Medical Human Genetics

Fig. 1

From: Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism

Fig. 1

A summary of the molecular rescues for PINK1/PARKIN loss of function. In the event of PINK1/Parkin loss of function, PINK1 remains embedded in the inner mitochondrial membrane with impaired kinase activity thus unable to phosphorylate PARKIN for translocation to the mitochondria. Respiratory complexes (ETS) drive the reactive oxygen species (ROS) cascade. ROS modify mitochondrial DNA and induce cytochrome C release to trigger apoptosis. Uncoupling protein 4 (UCP4) enables the leakage of protons from the intermembrane space back into the matrix where they combine with hydroxyl radicals (OH) and neutralize them. The chaperone proteins tumor necrosis factor receptor associated protein-1 (TRAP1) and carboxyl terminus of Hsc70-interacting protein (CHIP) promote the proper assembly of respiratory complex units in attempt to prevent the leakage of electrons from complex I which would trigger the ROS cascade. CHIP also inhibits protein misfolding. While PARKIN fails to ubiquitinate mitofusins (Mfn) and inhibit fusion, the mitochondrial ubiquitin ligase (MUL1) ubiquitinates Mfn and primes it for proteasomal degradation (UPS). By inhibiting fusion, mitochondria with damaged genomes do not infiltrate those that are healthy/functional. Autophagy related gene 1 (Atg-1) and four-wheel drive (Fwd) kinase promote mitochondrial fission resulting in sequestration of damaged mitochondria by mitophagy. Ectopic expression of the extracellular ligand wingless-related integration site (Wnt) promotes the transcriptional activity of peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC1α) and forkhead box O (FOXO). PGC1α is transiently inhibited by the protein PARIS (which would otherwise be degraded by the PINK1/Parkin axis). TRAP1 has also been shown to inhibit FOXO activity. However, upon induction via the Wnt signal, PGC1α and FOXO are activated to promote the transcription of antioxidant enzymes such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPX1). SOD2 and GPX1 scavenge ROS furthermore inhibiting ROS-induced stress such as apoptosis

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