Role of Pink1-mediated mitophagy in adenomyosis

Abstract

Background Recent studies indicate that endometrial hypoxia plays a critical role in adenomyosis (AM) development. Mitochondria are extremely sensitive to hypoxic damage, which can result in both morphological and functional impairment. Mitophagy is a crucial mechanism for preserving mitochondrial quality by selectively removing damaged mitochondria, thus ensuring the proper functioning of the entire mitochondrial network. In response to hypoxia, PINK1 is activated as a regulator of mitophagy, but its role in AM requires further study. Objective To explore the potential mechanism of mitophagy mediated by PINK1 in the pathogenesis of AM. Method The study compared PINK1, Parkin, OPTIN, P62, and NDP52 protein expression levels in patients with or without AM using clinical specimens and an AM mouse model. Pathological changes were compared using HE staining. Immunofluorescence and western blot were used to detect protein expression levels. Endometrial stromal cells (ESC) were isolated and examined for mitophagy, protein expression level, and cell invasion ability. Results Both the endometrial tissue from patients with AM and AM ESC displayed an upregulation of protein levels for PINK1, Parkin, OPTIN, P62, and NDP52 when compared with the control group. Then, HE staining confirmed the successful establishment of the AM mouse model. Moreover, the ultrastructural analysis using transmission electron microscopy revealed that AM mice’s endometrial glandular epithelial and stromal cells had exhibited swollen, deformed, and reduced mitochondria along with an increase in the number of lysosomes and mitochondrial autophagosomes. The protein levels of PINK1, Parkin, OPTIN, P62, and NDP52 in uterine tissue from AM mice were noticeably increased, accompanied by a considerable upregulation of ROS levels compared to the control group. In addition, cells in the AM group showed remarkably elevated mitophagy and invasion potentials compared to the control group. In contrast, the cell invasion ability decreased following PINK1 knockdown using the RNA interference technique. Conclusion The high levels of PINK1-mediated mitophagy have been found in AM. The upregulation in mitophagy contributes to mitochondrial damage, which may result in the abnormal invasion characteristic of AM.

Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease

“…a regulator of mitophagy, confirming the suitable functioning of the total mitochondria network [29]. Various stressors, such as hypoxia, ischemia, ageing, and oxidative stress may lead to an increase in ROS and damages to mitochondria, which may trigger the PINK1 mediated mitophagy [30].…”

“…Therefore, mitophagy might be a key mechanism for preserving the quality of mitochondria by eliminating damaged mitochondria. In response to hypoxia, the PTEN-induced putative kinase 1 (PINK1) may be activated as a regulator of mitophagy, confirming the suitable functioning of the total mitochondrial network [29]. Various stressors, such as hypoxia, ischemia, ageing, and oxidative stress, may lead to an increase in ROS and damages to mitochondria, which may trigger the PINK1 mediated mitophagy [30].…”