Perturbation in liver mitochondrial Ca2+ homeostasis in experimental iron overload: a possible factor in cell injury.
The functional state of isolated mitochondria and specifically the integrity of the inner membrane, were investigated in the liver of rats made siderotic by dietary supplementation with carbonyl iron. The concentration of iron in the hepatic tissue increased progressively up to nearly 40 days and reached a steady-state level. When the iron content reached a threshold value (higher than 90 nmol/mg protein) the occurrence of in vivo lipid peroxidation in the mitochondrial membrane was detected. This process did not result in gross alterations in the mitochondrial membrane, as indicated by electron microscopy, phosphorylative capability and membrane potential measurements. On the contrary, the induction of lipoperoxidative reaction appeared to be associated with the activation of Ca2+ release from mitochondria. This was shown to occur as a consequence of rather subtle modifications in the inner membrane structure via a specific efflux route, which appeared to be linked to the oxidation level of mitochondrial pyridine nucleotides. The induction of this Ca2+ release from iron-treated mitochondria resulted in enhancement of Ca2+ cycling, a process which dissipates energy to reaccumulate into mitochondria the released Ca2+. The perturbation in mitochondrial Ca2+ homeostasis reported here may be a factor in the onset of cell damage in this experimental model of hepatic iron overload.
Masini
A
A
Istituto di Patologia Generale, Università di Modena, Italy.
Ceccarelli
D
D
Trenti
T
T
Corongiu
F P
FP
Muscatello
U
U
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D007425:Intracellular Membranes / Q000502:physiology; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008564:Membrane Potentials; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012806:Siderosis / Q000378:metabolism* / Q000473:pathology
D009243:NAD; D009249:NADP; D007501:Iron; D005978:Glutathione; D002118:Calcium