Effects of AURKA‐mediated degradation of SOD2 on mitochondrial dysfunction and cartilage homeostasis in osteoarthritis

Abstract

This study aimed to investigate the mechanism of the ubiquitinase Aurora kinase A (AURKA) in the occurrence of osteoarthritis (OA) by mediating mitochondrial stress. Bioinformatic predictions revealed 2247 differentially expressed genes (DEGs) in the normal and OA tissues. According to the UbiNet database, 39 DEGs that code for ubiquitination enzymes was screened. AURKA was highly expressed in OA tissues and cells. AURKA interference inhibited the elevation of matrix metalloproteinase‐13 (MMP‐13). (MMP13), sex determining region Y‐box 9 (Sox9), and a disintegrin and metalloproteinase with thrombospondin motifs‐5 (ADAMTS5) expression and the reduction of collagen type IIα (Col2a1) and Aggrecan expression in interleukin‐1 β (IL‐1β) induced chondrocytes. The animal experiments proved that depleting AURKA could repress the occurrence of OA. Superoxide dismutase 2 (SOD2) was determined to be AURKA ubiquitination substrate via AURKA expression and bioinformatic prediction experiments. SOD2 expression was lower in OA tissues, but higher in normal joint tissues. AURKA interference activates SOD2. Meanwhile, the IP results confirmed that AURKA could bind to SOD2 and degrade it through K48 ubiquitination. Modification and overexpression of AURKA reduce SOD2 levels. AURKA interference can reverse the reactive oxygen species elevation caused by SOD2 overexpression or lysine‐48 (K48) mutation, respectively, leading to mitochondrial dysfunction. Furthermore, AURKA silencing suppressed the occurrence of OA induced by mitochondrial activation. These findings suggest that ubiquitination of AURKA lowers SOD2 expression and affects mitochondrial dysfunction to repress the occurrence of OA. The results of the current study reveal that AURKA ubiquitination influences mitochondrial dysfunction and suppresses the occurrence of OA via degradation of SOD2. These data reveal novel potential targets for OA treatment

Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases

“…Cell cycle analysis also demonstrated that aurora kinase inhibition produced a significant increase in cells with 4N and higher DNA content, consistent with the mechanism of these agents in inducing mitotic arrest, which also translated into an increase in cellular senescence. Moreover, tozasertib induced generation of ROS and mitochondrial dysfunction, counteracting one of the carcinogenic mechanisms of aurora kinases in antagonizing ROS production [ 3 , 9 , 41 , 42 ], which was blocked by NAC.…”

“…Aurora kinase inhibition has been shown to alter various antioxidant enzymes such as superoxide dismutase and catalase, which are important to maintain proper cellular redox states [41,42]. The impact of mitochondrial activities on cellular physiology is not only restricted to ATP production, but also the generation of reactive oxygen species [43].…”

Glycolysis-related gene expression profiling serves as a novel prognosis risk predictor for human hepatocellular carcinoma

“…It is located in the mitochondrial membrane where it regulates mitochondrial dynamics and ATP production 46 , 47 . AURKA is an effective prognostic indicator that probably integrates multiple oncogenic events in progression of tumors 43 , 48 , 49 . CDK1 (Cyclin-dependent kinase 1) is a serine/threonine-like protein kinase that plays an essential role in controlling cell proliferation at the G2/M point of the cell cycle.…”

D‐mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF‐2α‐dependent manner

“…It is known that articular cartilage damage is the most obvious pathologic feature leading to joint dysfunction. Earlier research reported several ferroptosis‐related features, such as abnormal iron metabolism, 10 , 11 , 37 , 38 lipid peroxidation 39 , 40 and mitochondrial dysfunction, 41 , 42 are closely correlated with accelerating cartilage destruction. It is only recently that Yao et al 9 first demonstrated that chondrocyte ferroptosis contributes to the progression of osteoarthritis.…”