Alkaline phosphatase responsive disulfide formation for transforming into fiber structure inside mitochondria of senescent cells

Abstract

The intracellular biomacromolecules including proteins, DNA, and polysaccharides, play an important role to perform cellular function. Theses macromolecules have specific structure synthesized by the self-assembly of small molecules such as amino acids, nucleotides, and monossacharides, but they have distinct properties that the small molecules do not have. Interestingly, the structure could be transformed into two or more alternative conformations under a given environment, which is related to multiple physiological activities of biological entities. From this perspective, understanding the mechanism of structural transformation could open a new chapter to explore artificial chemical system that imitates bioprocesses. Herein, we developed intracellular transformable assembly system via disulfide formation, in which the spherical structure (inactive form) would be transformed into the fiber structure (active form) for regulating cellular fate. The designed monomer, in which the thiol groups were blocked by phosphate groups, did not form a disulfide bond and assembled into a spherical structure in a zwitterionic form. The p-Mito-1 undergoes rapid dephosphorylation catalyzed by ALP to form Mito-1, thereby accumulating into mitochondria and transforming into fiber structure through disulfide formation by reactive oxygen species (ROS). The resulting fiber structure disrupted the mitochondrial membrane, leading to activation of apoptotic signaling toward senescent cell.