Iowa Mutant Apolipoprotein A-I (ApoA-I(Iowa)) Fibrils Target Lysosomes

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-I(Iowa)) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-I(Iowa) fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-I(Iowa) fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-I(Iowa) fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-I(Iowa) fibrils. Thus, although apoA-I(Iowa) fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-I(Iowa) fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-I(Iowa) fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.