Chaperone-mediated autophagy (CMA)

Chaperone-mediated autophagy (CMA) is a precise way your cells recycle individual proteins. Unlike bulk autophagy, it does not wrap cargo in a vesicle. Instead, it ferries one tagged protein at a time straight into the lysosome (the cell's recycling chamber). The tag is a specific motif (a KFERQ-like sequence, recognized by its charge pattern rather than exact letters). A chaperone protein called HSC70 (always present, made by the HSPA8 gene) grabs that motif, with help from co-chaperones. The complex then docks at the lysosome through a receptor called LAMP2A, the one receptor that is enough for CMA. LAMP2A briefly clusters to form a channel the protein slides through. With age, LAMP2A levels at the lysosome fall, partly because changes in lysosomal fats speed its breakdown. That slows CMA and lets damaged, clump-prone proteins build up. Zhang and Cuervo (2008) showed the link in aged rodents: keeping liver LAMP2A high restored CMA, improved protein quality control, and preserved liver metabolism, causal evidence that CMA decline drives age-related proteostasis loss. The strongest evidence is in rodent liver and neurons. Human aging data are still limited. A 2024 review by Endicott cautioned that the size and universality of the decline vary by tissue and genetic background, so be careful extrapolating across species or cell types.

Last reviewed: June 22, 2026

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