Cadmium activates a programmed, lysosomal membrane permeabilization-dependent necrosis pathway.
Cadmium is a highly toxic, carcinogenic, and atherogenic element. A central principle in many Cd-induced pathophysiologies is the induction of cell death. In past studies Cd was shown to cause apoptosis, necrosis, programmed necrosis, or autophagy. This study was conducted to precisely define the end stage processes and outcome of Cd-induced cell death in endothelial cells (ECs). We show that Cd leads to acidification and permeabilization of lysosomes, followed by the release of active DNAse II from lysosomes. The absence of nuclear DNA due to DNAse II activity may have lead to misinterpretations of the type of cell death outcome in previous studies. Further, Cd-induced cell death is characterized by a massive release of lactate dehydrogenase (LDH), a gold standard marker for the occurrence of plasma membrane rupture i.e. necrosis. Importantly, lentivirus-based over-expression of the anti-apoptotic protein BCL-XL abrogates lysosomal rupture, DNA degradation and LDH release, clearly indicating that Cd induces a programmed form of cell death with a necrotic endpoint.
Surgical Research Laboratories - Cardiac Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria. Barbara.Messner@meduniwien.ac.at
Barbara
B
Messner
Christian
C
Ploner
Günther
G
Laufer
David
D
Bernhard
D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D051020:bcl-X Protein / Q000378:metabolism
D002273:Carcinogens; D051020:bcl-X Protein; D002104:Cadmium; D007770:L-Lactate Dehydrogenase; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II