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 enhances their sensitivity to oxidative stress. This is explained by compensatory autophagocytosis, which results in increased amounts of lysosomal low-molecular-weight, redox-active iron, due to the degradation of metallo-proteins, with a potential increase in iron-catalyzed, intralysosomal oxidative reactions. Such reactions diminish the stability of lysosomal 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 remarkably sensitive to oxidative stress, actually attenuated the sensitivity to such stress. We found that starved NIT cells rapidly synthesized ferritin. Moreover, ferritin was found to be autophagocytosed, and the lysosomes were stabilized, as assayed by the acridine orange relocation test. We hypothesize that compensatory autophagocytosis during starvation increases the cytosolic pool of redox-active iron, as a reflection of enhanced transportation of low-molecular-weight iron from autophagic lysosomes to the cytosol, resulting in ferritin induction. The newly formed ferritin would, in turn, become autophagocytosed and bind redox-active lysosomal iron in a non-redox-active form. We also suggest that the proposed mechanism may be a way for oxidative stress-sensitive 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 beta cell may belong to this type of cells.
Olejnicka
B T
BT
Department of Pathology II, Faculty of Health Sciences, Linköping University, Sweden. olejnicka@pat.liu.se
Dalen
H
H
Baranowski
M M
MM
Brunk
U T
UT
D000818:Animals; D001343:Autophagy; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D005293:Ferritins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007340:Insulinoma / Q000473:pathology / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D014407:Tumor Cells, Cultured
D016895:Culture Media, Serum-Free; D005293:Ferritins; D006861:Hydrogen Peroxide