Ros

(Tchaperonins Hsp60 Hsc70

Mitochondria >1000

aA crystallin o Oxidation of folding proteins

Accumulation of misfolded proteins

Lysosome

Lysosome

Lipophilic toxins lipofuscin aA crystallin

Apoptosis

Accumulation of misfolded proteins sHsp's o

Chaperone-mediated autophagy

Unfolded proteins

Chaperone ^ mediated protein import and folding Proteasome-mediated protein degradation

Chaperone-mediated autophagy sHsp's o o o

Unfolded proteins

Figure 44.1 Roles of subcellular chaperones during aging. Various environmental stressors lead to protein damage and misfolded proteins that bind to chaperones within the various cellular compartments. Irreversibly damaged proteins are targeted for degradation. If degradation is impaired and if there is an increase in protein damage, the chaperone systems might be overwhelmed, compromising the cell's ability to function properly. Also, chaperones might be damaged, leading to their removal and subsequent up-regulation. These events might trigger the senescent phenotype, and consequently, gradual tissue dysfunction.

the matrix or inner membrane. The physiological importance of these changes is an increased capacity for import into the organelle at any given precursor concentration. Defects in the protein import machinery components have been associated with mitochondrial disorders (Hood and Joseph, 2004) During synthesis of ATP in mitochondria, reactive oxygen species (ROS) are generated that are detrimental to mitochondrial and cellular function that with time contributes to the aging process. Chaperone species within the mitochondria could slow down the damage caused by ROS and participate in mitochondrial protein biogenesis (Voos and Rottgers, 2002).

Lysosomal chaperones Physiological stresses such as prolonged starvation lead to chaperone-mediated autophagy (CMA) whereby a lysosomal pathway of proteolysis is activated (Majeski and Dice, 2004).

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