Chondrocytes are responsible for the maintenance of the articular cartilage. A loss of homeostasis in cartilage contributes to the development of osteoarthritis (OA) when the synthetic capacity of chondrocytes is overwhelmed by processes that promote matrix degradation. There is evidence for an age-related imbalance in reactive oxygen species (ROS) production relative to the anti-oxidant capacity of chondrocytes that plays a role in cartilage degradation as well as chondrocyte cell death. The ROS produced by chondrocytes that have received the most attention include superoxide, hydrogen peroxide, the reactive nitrogen species nitric oxide, and the nitric oxide derived product peroxynitrite. Excess levels of these ROS not only cause oxidative-damage but, perhaps more importantly, cause a disruption in cell signaling pathways that are redox-regulated, including Akt and MAP kinase signaling. Age-related mitochondrial dysfunction and reduced activity of the mitochondrial superoxide dismutase (SOD2) are associated with an increase in mitochondrial-derived ROS and are in part responsible for the increase in chondrocyte ROS with age. Peroxiredoxins (Prxs) are a key family of peroxidases responsible for removal of HO, as well as for regulating redox-signaling events. Prxs are inactivated by hyperoxidation. An age-related increase in chondrocyte Prx hyperoxidation and an increase in OA cartilage has been noted. The finding in mice that deletion of SOD2 or the anti-oxidant gene transcriptional regulator nuclear factor-erythroid 2- related factor (Nrf2) result in more severe OA, while overexpression or treatment with mitochondrial targeted anti-oxidants reduces OA, further support a role for excessive ROS in the pathogenesis of OA. Therefore, new therapeutic strategies targeting specific anti-oxidant systems including mitochondrial ROS may be of value in reducing the progression of age-related OA.
2-Cys peroxiredoxins (Prxs) modulate hydrogen peroxide (HO)-mediated cell signaling. At high HO levels, eukaryotic Prxs can be inactivated by hyperoxidation and are classified as sensitive Prxs. In contrast, prokaryotic Prxs are categorized as being resistant to hyperoxidation and lack the GGLG and C-terminal YF motifs present in the sensitive Prxs. Additional molecular determinants that account for the subtle differences in the susceptibility to hyperoxidation remain to be identified. A comparison of a new, 2.15-Å-resolution crystal structure of Prx2 in the oxidized, disulfide-bonded state with the hyperoxidized structure of Prx2 and Prx1 in complex with sulfiredoxin revealed three structural regions that rearrange during catalysis. With these regions in hand, focused sequence analyses were performed comparing sensitive and resistant Prx groups. From this combinatorial approach, we discovered two novel hyperoxidation resistance motifs, motifs A and B, which were validated using mutagenesis of sensitive human Prxs and resistant serovar Typhimurium AhpC. Introduction and removal of these motifs, respectively, resulted in drastic changes in the sensitivity to hyperoxidation with Prx1 becoming 100-fold more resistant to hyperoxidation and AhpC becoming 800-fold more sensitive to hyperoxidation. The increased sensitivity of the latter AhpC variant was also confirmed These results support the function of motifs A and B as primary drivers for tuning the sensitivity of Prxs to different levels of HO, thus enabling the initiation of variable signaling or antioxidant responses in cells.
Peroxiredoxins (Prdxs) sense and assess peroxide levels, and signal through protein interactions. Understanding the role of the multiple structural and post-translational modification (PTM) layers that tunes the peroxiredoxin specificities is still a challenge. In this review, we give a tabulated overview on what is known about human and bacterial peroxiredoxins with a focus on structure, PTMs, and protein-protein interactions. Armed with numerous cellular and atomic level experimental techniques, we look at the future and ask ourselves what is still needed to give us a clearer view on the cellular operating power of Prdxs in both stress and non-stress conditions.
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