mTORC1 activation contributes to autophagy inhibition via its recruitment to lysosomes and consequent lysosomal dysfunction in cadmium-exposed rat proximal tubular cells.

mTORC1 activation contributes to autophagy inhibition via its recruitment to lysosomes and consequent lysosomal dysfunction in cadmium-exposed rat proximal tubular cells.
J Inorg Biochem. 2020 Aug 21;212:111231
Authors: Lian CY, Yang H, Zhai ZZ, Li ZF, Han DG, Wang L
Abstract
Autophagy dysregulation is implicated in cadmium (Cd)-induced nephrotoxicity. The mammalian target of rapamycin complex 1 (mTORC1) is a negative regulator of autophagy, but its role in Cd-induced autophagy inhibition and possible regulatory mechanisms remains poorly understood. In the present study, Cd exposure activated mTORC1 in primary rat proximal tubular (rPT) cells, and two mTORC1 inhibitors (rapamycin and torin 1) were separately utilized to inhibit Cd-induced mTORC1 activation. Data showed that Cd-inhibited autophagic flux was markedly restored by two mTORC1 inhibitors, respectively, as evidenced by immunoblot analysis of autophagy marker proteins and tandem red fluorescent protein-green fluorescent protein-microtubule associated protein light chain 3 (RFP-GFP-LC3) fluorescence microscopy assay. Importantly, Cd exposure triggered the recruitment of mTORC1 onto lysosome membrane assessed by immunofluorescence co-localization analysis, which was obviously inhibited by rapamycin or torin 1. Moreover, Cd-induced lysosomal alkalization, suppressed vacuolar ATPases (V-ATPases) protein levels and impaired lysosomal degradation capacity were markedly reversed by...

Source: Journal of Inorganic Biochemistry - August 20, 2020 Category: Biochemistry Authors: Lian CY, Yang H, Zhai ZZ, Li ZF, Han DG, Wang L Tags: J Inorg Biochem Source Type: research