Mitochondrial permeability transition induced DNA-fragmentation in the rat hippocampus following hypoglycemia

In the present study the time-course of DNA fragmentation following insulin-induced hypoglycemia was examined. In situ localization of DNA breaks were studied by the terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labelling method, and the temporal profile of DNA-fragmentation by agarose gel electrophoresis. Cell nuclei displayed terminal deoxynucleotidyl transferase-deoxyuridine triphosphate nick-end labelling within 3 h of recovery following 30 min of a hypoglycemic insult, and DNA from the hippocampus displayed oligonucleosomal fragmentation. Ultrastructural examination of the dentate granule cells showed mitochondrial swelling during the acute phase of the hypoglycemic insult, which preceded the DNA fragmentation seen in the recovery phase. Cyclosporin A but not tacrolimus, prevented mitochondrial swelling and subsequent DNA fragmentation. We conclude that during severe energy deprivation following hypoglycemia, mitochondrial swelling occurs due to mitochondrial permeability transition and that factors are released, which upon recovery can activate processes leading to DNA fragmentation and cell death.