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

SOD2 基因沉默 阿格里坎 癌症研究 阿达姆斯 泛素 生物 化学 骨关节炎 细胞生物学 基质金属蛋白酶 分子生物学 氧化应激 超氧化物歧化酶 金属蛋白酶 医学 病理 内分泌学 生物化学 血栓反应素 基因 替代医学 关节软骨
作者
Cheng Yang,Di You,Jun Huang,Bo Yang,Xianzhe Huang,Jiangdong Ni
出处
期刊:Journal of Cellular Physiology [Wiley]
卷期号:234 (10): 17727-17738 被引量:30
标识
DOI:10.1002/jcp.28398
摘要

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.
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