Senescent cell survival relies on upregulation of lysosomal quality control mechanisms
Carroll, B.; Curnock, R.
Show abstract
The accumulation of senescent cells is a key mediator of tissue and organismal ageing. Persistent activation of the growth regulator, mTORC1, even in the absence of growth factors and amino acids, supports senescence phenotypes, such as increased cell size and secretion of inflammatory factors. Here we extend this finding to show that senescence is associated with lysosomal accumulation of the low-density lipoprotein receptor (LDLR) and a failure of mTORC1 signalling to respond to changes in cholesterol. These observations are reflective of a broader dysfunction through the endo-lysosomal pathway, with Rab GTPases and phosphoinositides localised to atypical hybrid organelles. We propose that endosomal mistrafficking, in concert with increased autophagy and elevated lysosomal pH are contributing to an accumulation of undegraded material and lysosomal membrane damage. Our data indicate that in response to lysosomal dysfunction, senescent cells not only upregulate TFEB/TFE3-dependent lysosomal quality control but also upregulate lysosomal repair via PI4K2A-dependent PITT pathway. Perturbation of the lipid transport machinery required for lysosomal repair caused senescent cell death, revealing that targeting mechanisms of lysosomal repair has senolytic potential.
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