Mitochondria possess a Ca transport system composed of separate Ca influx and efflux pathways. Intramitochondrial Ca concentrations regulate oxidative phosphorylation, required for cell function and survival, and mitochondrial redox balance, that participates in a myriad of signaling and damaging pathways. The interaction between Ca accumulation and redox imbalance regulates opening and closing of a highly regulated inner membrane pore, the membrane permeability transition pore (PTP). In this review, we discuss the regulation of the PTP by mitochondrial oxidants, reactive nitrogen species, and the interactions between these species and other PTP inducers. In addition, we discuss the involvement of mitochondrial redox imbalance and PTP in metabolic conditions such as atherogenesis, diabetes, obesity and in mtDNA stability.

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Iron imbalance/accumulation has been implicated in oxidative injury associated with many degenerative diseases such as hereditary hemochromatosis, β-thalassemia, and Friedreich's ataxia. Mitochondria are particularly sensitive to iron-induced oxidative stress -high loads of iron cause extensive lipid peroxidation and membrane permeabilization in isolated mitochondria. Here we detected and characterized mitochondrial DNA damage in isolated rat liver mitochondria exposed to a Fe 2+ -citrate complex, a small molecular weight complex. Intense DNA fragmentation was induced after the incubation of mitochondria with the iron complex. The detection of 3' phosphoglycolate ends at the mtDNA strand breaks by a 32 P-postlabeling assay, suggested the involvement of hydroxyl radical in the DNA fragmentation induced by Fe 2+ -citrate. Increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine also suggested that Fe 2+ -citrate-induced oxidative stress causes mitochondrial DNA damage. In conclusion, our results show that iron-mediated lipid peroxidation was associated with intense mtDNA damage derived from the direct attack of reactive oxygen species.