Possible involvement of mitochondrial calcium transport in causing cell injury in experimental hepatic chronic iron overload

The functional state of isolated mitochondria and, specifically, the integrity of the inner membrane were investigated in the livers of rats made siderotic by dietary supplementation with carbonyl iron. The concentration of iron in the mitochondrial fraction increased progressively up to nearly 40 days and it reached a steady-state level. When the iron content reached a threshold value (higher than 30 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 phosphorylative capability and membrane potential measurements. On the contrary, the induction of the 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 the releaased Ca²⁺ into mitochondria. The perturbation in mitochondrial Ca²⁺ homeostasis reported here may be a factor in the onset of cell damage in this experimental model of hepatic chronic iron overload.