Loss of hepatic chaperone‐mediated autophagy accelerates proteostasis failure in aging

Abstract

Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging. Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

“…Crosstalk between both autophagic pathways has been extensively reported both in vivo and in vitro , whereby one reacts in a compensatory manner to the loss of activity in the other [8,46,48]. However, in this work we show that the functional connection between NFE2L2 and CMA is independent of macroautophagy.…”

“…Although it is possible that higher levels of HSPA8 are a result of the relative decrease in lysosomal cargoes, we cannot discard the possibility that the increase in lysosomal HSPA8 may represent a compensatory mechanism to counteract the decrease in LAMP2A levels. In fact, increased HSPA8 levels have been previously reported in other conditions with reduced lysosomal levels of LAMP2A, such as livers from old mice and in lamp2a- KO mice [25,46]. …”

“…Both CMA [25,46] and NFE2L2 [49,50] activities decline with age, probably favoring the accumulation of oxidized substrates. A wide variety of NFE2L2 inducers have been reported, and in fact, in this study we successfully used SFN to increase Lamp2a mRNA and protein levels and increase CMA activity.…”

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

“…Upregulation of CMA upon mild oxidative stress facilitates degradation of oxidized proteins (52) that otherwise will aggregate and persist as intracellular protein inclusions (17). This explains why CMA blockage associates with an increase in intracellular protein aggregates (17,56) and why old mice with preserved CMA activity show reduction in the age-dependent increase in aggregate oxidized proteins (76).…”

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

“…Defective autophagy reduces the lifespan, whereas induction of autophagy can increase longevity in multiple animal species (Madeo, Tavernarakis, & Kroemer, 2010; Rubinsztein, Marino, & Kroemer, 2011). In aged livers, autophagy activity is decreased, while the restoration of autophagy has been shown to improve cellular maintenance and hepatic function (Schneider et al., 2015; Zhang & Cuervo, 2008). …”