Figure 12.

A model depicting the role of albumin as an extracellular PP-IX trap, thereby modulating PP-IX-mediated proteotoxicity and cellular damage. PP-IX biosynthesis is initiated in the mitochondria through a multistep mechanism, and is excreted by transporters (FLVCR1a, ABCG2, ABCB6). When the rate of PP-IX synthesis exceeds the rate of PP-IX excretion, PP-IX accumulates intracellularly thereby causing organelle-selective protein aggregation. Lysosomes are protected from PP-IX-mediated protein aggregation since PP-IX speciates into biologically inert higher-order structures in its acidic pH. Extracellular PP-IX-binding proteins, such as with albumin, may serve as a “PP-IX sponge” and shift the equilibrium of PP-IX excretion. Thus, in the presence of albumin, there is less intracellular PP-IX retention and protein aggregation. C-gen, coproporphyrinogen; U-gen, uroporphyrinogen.