Mitochondrial Sco proteins are involved in oxidative stress defense

Abstract

Members of the evolutionary conserved Sco protein family have been intensively studied regarding their role in the assembly of the mitochondrial cytochrome c oxidase. However, experimental and structural data, specifically the presence of a thioredoxin-like fold, suggest that Sco proteins may also play a role in redox homeostasis.In our study, we addressed this putative function of Sco proteins using Saccharomyces cerevisiae as a model system. Like many eukaryotes, this yeast possesses two SCO homologs (SCO1 and SCO2). Mutants bearing a deletion of either of the two genes are not affected in their growth under oxidative stress. However, the concomitant deletion of the SOD1 gene encoding the superoxide dismutase 1 resulted in a distinct phenotype: double deletion strains lacking SCO1 or SCO2 and SOD1 are highly sensitive to oxidative stress and show dramatically increased ROS levels.The respiratory competent double deletion strain Δsco2Δsod1 paved the way to investigate the putative antioxidant function of SCO homologs apart from their role in respiration by complementation analysis. Sco homologs from Drosophila, Arabidopsis, human and two other yeast species were integrated into the genome of the double deletion mutant and the transformants were analyzed for their growth under oxidative stress. Interestingly, all homologs except for Kluyveromyces lactis K07152 and Arabidopsis thaliana HCC1 were able to complement the phenotype, indicating their role in oxidative stress defense. We further applied this complementation-based system to investigate whether pathogenic point mutations affect the putative antioxidant role of hSco2. Surprisingly, all of the mutant alleles failed to restore the ROS-sensitivity of the Δsco2Δsod1 strain.In conclusion, our data not only provide clear evidence for the function of Sco proteins in oxidative stress defense but also offer a valuable tool to investigate this role for other homologous proteins.

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…Of note, endothelial cells consume a slight amount of oxygen to produce ATP in order to transfer most of the oxygen to myocardium [45,46]. In vitro data suggest superoxide generated by mitochondria accounts for 0.2-2% of cellular oxygen consumption [47,48]. It has been found that endothelial cell dysfunction affects the diffusion rate of oxygen across the arteriolar vessel wall [49,50]; however, these observations require further discussion.…”

Recurrent Sequence Evolution After Independent Gene Duplication

“…To these we The precise functional differentiation between Sco1 and Sco2 in different species remains unknown despite various direct experimental studies [52,53,54]. New evidence suggests that they may have "distinct antioxidant capacity" in addition to their partially redundant roles in cytochrome c oxidase assembly [55]. Both are localized to the mitochondrion, but their specific location within the mitochondrial matrix could be different as a consequence of the indels in the target sequence and matrix region.…”

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

“…Azoramide reduces the increase in ROS and ameliorates the decline in mitochondrial membrane potential in PLA2G6 D331Y/D331Y midbrain DA neurons Oxidative stress causes the release of cytochrome c from mitochondria, which activates the apoptotic pathway [21][22][23][24][25] . Intracellular ROS in DA neurons was measured with the fluorescent probe CellROX® Green Reagent.…”