The mammalian target of rapamycin regulates mitochondrial homeostasis and cellular senescence through the autophagy adaptor p62/SQSTM1

Alessandro Bitto

doi:10.17918/00000481

All living organisms are subject to progressive loss of function and damage to their tissues, a process known as aging. At the cellular level, the accumulation of damage to DNA, proteins, and organelles induces cellular senescence, a stress-response pathway that likely influence the aging process, because of its involvement in age-related pathologies and in reducing the lifespan of transgenic mice affected by a progeroid syndrome. Aging can be delayed by single gene mutations in the Insulin/IGF-1 and TOR pathways. These mutations affect the activity of cellular pathways that increase cellular homeostasis, such as stress-resistance, protein folding, and protein and organelle degradation. Among these pathways, autophagy plays a critical role in mediating the anti-aging effects of long-lived mutations in the Insulin/IGF-1 and TOR pathways. Autophagy of damaged proteins and organelles is mediated by p62/SQSTM1, a multi-domain protein involved in several signaling and degradation pathways. Loss of p62/SQSTM1 reduces lifespan and causes age-related pathologies in mouse, suggesting its involvement in the aging process. Nevertheless, it remains unknown whether p62/SQSTM1 is required to extend lifespan in response to reduced Insulin/IGF1 and TOR signaling, nor whether these pathways extend lifespan by modulating cellular senescence. We explored the role of the IGF-1 and mTOR signaling pathways in cellular senescence. Prolonged exposure to IGF-1 activates mTOR, promotes cellular senescence and reduces proliferative potential in quiescent human fibroblasts by reducing the autophagy of depolarized mitochondria. Similarly, proliferating cells progressively accumulate depolarized mitochondria and show increased signaling through mTOR as they approach replicative senescence. Inhibiting mTOR with rapamycin restores the autophagy of depolarized mitochondria, restores proliferative potential in cells treated with IGF-1, and delays the onset of cellular senescence in quiescent and proliferating cells. In addition, rapamycin reduces the accumulation of reactive oxygen species and increases resistance to exogenous stress by inducing the NFE2L2 anti-oxidant response. Reducing the expression of p62/SQSTM1 abrogates mitochondrial clearance and the activation of NFE2L2 in cells treated with rapamycin, and promotes the expression of markers of senescence. Our results provide a link between mTOR signaling and cellular senescence, and establish p62/SQSTM1 as a mediator of longevity in response to mTOR inhibition.

The mammalian target of rapamycin regulates mitochondrial homeostasis and cellular senescence through the autophagy adaptor p62/SQSTM1

Files and links (1)

Abstract

Metrics

Details

The mammalian target of rapamycin regulates mitochondrial homeostasis and cellular senescence through the autophagy adaptor p62/SQSTM1

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media