STARVATION-INDUCED AUTOPHAGOCYTOSIS PARADOXICALLY DECREASES THE SUSCEPTIBILITY TO OXIDATIVE STRESS OF THE EXTREMELY OXIDATIVE STRESS-SENSITIVE NIT INSULINOMA CELLS

Glucose and amino acid starvation of cells in culture generally enhanc es their sensitivity to oxidative stress. This is explained by compens atory autophagocytosis, which results in increased amounts of lysosoma l low-molecular-weight, redox-active iron, due to the degradation of m etallo-proteins, with a potential increase in iron-catalyzed, intralys osomal oxidative reactions. Such reactions diminish the stability of l ysosomal membranes, with resultant leakage of hydrolytic enzymes into the cytosol and ensuing cellular degeneration, often of apoptotic type . However, starvation of NIT insulinoma cells, which are normally rema rkably sensitive to oxidative stress, actually attenuated the sensitiv ity to such stress, We found that starved NIT cells rapidly synthesize d ferritin. Moreover, ferritin was found to be autophagocytosed, and t he lysosomes were stabilized, as assayed by the acridine orange reloca tion test. We hypothesize that compensatory autophagocytosis during st arvation increases the cytosolic pool of redox-active iron, as a refle ction of enhanced transportation of low-molecular-weight iron from aut ophagic lysosomes to the cytosol, resulting in ferritin induction. The newly formed ferritin would, in turn, become autophagocytosed and bin d redox-active lysosomal iron in a non-redox-active form. We also sugg est that the proposed mechanism may be a way for oxidative stress-sens itive cells to compensate partly for their failing capacity to degrade hydrogen peroxide before it leaks into the acidic vacuolar apparatus and induces intralysosomal oxidative stress. The insulin-producing bet a cell may belong to this type of cells.