Mitochondrial changes and associated alterations induced in mice by streptozotocin administered in vivo and in vitro.
Isolated mouse liver mitochondria incubated with streptozotocin showed decreased rate and extent of Ca2+ uptake, and, dependent on the concentration of streptozotocin and the addition of alpha-ketoglutarate, glutamate, fluorocitrate or guanosine 5'-triphosphate, the retention of Ca2+ was either increased or decreased. Similar observations were made in liver mitochondria incubated with succinyl-CoA. In mitochondria isolated from the kidneys and islets of mice injected with streptozotocin, with and without additional injections of glucose and/or glucagon, the rate and extent of Ca2+ uptake were reduced and the release of accumulated Ca2+ was stimulated. Electron microscopy and X-ray microanalysis showed dislocation of Ca2+-containing precipitates from the mitochondria to the cytosol, and stereology disclosed increased mitochondrial volume in the B cells of streptozotocin-treated mice. State 3 and state 4 respiration with NAD-linked substrates was inhibited, but succinate oxidation was unaffected, in mitochondria isolated from the kidneys of mice treated with streptozotocin. In the kidneys of streptozotocin-injected mice, the concentration of succinyl-CoA was increased, that of citrate and guanosine 5'-triphosphate was decreased, that of glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-diphosphate was unaffected, and the metabolite concentration ratios suggested increased mitochondrial [NAD+]/[NADH] ratio and decreased cytoplasmic [NAD+]/[NADH] ratio. It is suggested as a new hypothesis that the cytotoxicity and the diabetogenicity of streptozotocin are dependent on inhibited citric acid cycle enzyme activity (primarily that of succinyl-CoA synthetase and citrate synthetase) with altered metabolite concentrations, leading to impairment of the mitochondrial uptake of Ca2+ and the activation of the pyruvate, isocitrate and alpha-ketoglutarate dehydrogenases.
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002951:Citrates / Q000494:pharmacology; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006160:Guanosine Triphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D013311:Streptozocin / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D002951:Citrates; D005971:Glutamates; D007656:Ketoglutaric Acids; C007744:fluorocitrate; D018698:Glutamic Acid; D013311:Streptozocin; D006160:Guanosine Triphosphate; D005934:Glucagon; C012046:succinyl-coenzyme A; D005947:Glucose; D002118:Calcium