Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway

• DOI: 10.1038/s41419-024-06540-w
• Publication Date: 2024-02-21T13:02:18Z
• Authors: Xing-Yu Zhou; Yun-Hui Lai; Jun Zhang; Ying Li; Xiao-Min Wu; Yi-Zhen Yang; Xiao-Fei Zhang; Lin-Zi Ma; Ke-Ming Zheng; Yu-Dong Liu; Zhe Wang; Shi-Ling Chen
• Keywords: Mammals; 0303 health sciences; Granulosa Cells; QH573-671; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; TOR Serine-Threonine Kinases; Article; Rats; 03 medical and health sciences; Advanced Oxidation Protein Products; Autophagy; Humans; Animals; Female; Cytology; Reactive Oxygen Species; Lysosomes

AbstractOxidative stress dysfunction has recently been found to be involved in the pathogenesis of premature ovarian insufficiency (POI). Previously, we found that advanced oxidation protein products (AOPPs) in plasma were elevated in women with POI and had an adverse effect on granulosa cell proliferation. However, the mechanism underlying the effects of AOPPs on autophagy-lysosome pathway regulation in granulosa cells remains unclear. In this study, the effect of AOPPs on autophagy and lysosomal biogenesis and the underlying mechanisms were explored by a series of in vitro experiments in KGN and COV434 cell lines. AOPP-treated rat models were employed to determine the negative effect of AOPPs on the autophagy-lysosome systems in vivo. We found that increased AOPP levels activated the mammalian target of rapamycin (mTOR) pathway, and inhibited the autophagic response and lysosomal biogenesis in KGN and COV434 cells. Furthermore, scavenging of reactive oxygen species (ROS) with N-acetylcysteine and blockade of the mTOR pathway with rapamycin or via starvation alleviated the AOPP-induced inhibitory effects on autophagy and lysosomal biogenesis, suggesting that these effects of AOPPs are ROS-mTOR dependent. The protein expression and nuclear translocation of transcription factor EB (TFEB), the key regulator of lysosomal and autophagic function, were also impaired by the AOPP-activated ROS-mTOR pathway. In addition, TFEB overexpression attenuated the AOPP-induced impairment of autophagic flux and lysosomal biogenesis in KGN and COV434 cells. Chronic AOPP stimulation in vivo also impaired autophagy and lysosomal biogenesis in granulosa cells of rat ovaries. The results highlight that AOPPs lead to impairment of autophagic flux and lysosomal biogenesis via ROS-mTOR-TFEB signaling in granulosa cells and participate in the pathogenesis of POI.