mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.

Trichloroethylene (TCE) is extensively utilized within industrial settings. Certain individuals with occupational exposure may develop occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT), with renal injury being a predominant clinical manifestation among OMDT patients. Prior research has demonstrated that TCE-sensitized mice exhibit glomerular podocyte damage and activation of the mTOR signaling pathway, although the precise mechanisms remain unclear. In the present study, we employed Rapamycin, an mTORC1 inhibitor, to intervene in a TCE-sensitized mouse model. This was complemented by TCE-sensitized mice serum-induced mouse podocyte clone-5 (MPC5) cell model to elucidate the mechanism through which mTORC1 contributes to podocyte damage during TCE sensitization. The findings indicate that activation of mTORC1 results in the downregulation of autophagy/beclin-1 regulator-1 (AMBRA1) expression. Following intervention with Rapamycin, there was a significant restoration of AMBRA1 expression in mice, accompanied by increased mitophagy and decreased apoptosis levels. In vitro studies using cell culture models demonstrated that MPC5 cells exposed to serum from TCE-sensitized mice showed markedly reduced expression of PINK1 and Parkin proteins, along with suppressed mitophagy levels. Treatment with Rapamycin or si-AMBRA1 effectively enhanced cellular mitophagy and diminished apoptosis. This study elucidates that TCE sensitization activates the mTORC1 signaling pathway, leading to the downregulation of AMBRA1. The suppression of AMBRA1 impedes the PINK1/Parkin-dependent mitophagy pathway, hindering the timely clearance of damaged mitochondria in podocytes. Consequently, this results in the release of cytochrome C into the cytoplasm, which triggers podocyte apoptosis signaling, compromises the integrity of the glomerular filtration barrier, and ultimately leads to renal dysfunction.