Increased Susceptibility ofGracilinanus microtarsusLiver Mitochondria to Ca2+-Induced Permeability Transition Is Associated with a More Oxidized State of NAD(P)
In addition to be the cell’s powerhouse, mitochondria also contain a cell death machinery that includes highly regulated processes such as the membrane permeability transition pore (PTP) and reactive oxygen species (ROS) production. In this context, the results presented here provide evidence that liver mitochondria isolated fromGracilinanus microtarsus, a small and short life span (one year) marsupial, when compared to mice, are much more susceptible to PTP opening in association with a poor NADPH dependent antioxidant capacity. Liver mitochondria isolated from the marsupial are well coupled and take upCa2+but exhibited a much lowerCa2+retention capacity than mouse mitochondria. Although the known PTP inhibitors cyclosporin A, ADP, and ATP significantly increased the marsupial mitochondria capacity to retainCa2+, their effects were much larger in mice than in marsupial mitochondria. Both fluorescence and HPLC analysis of mitochondrial nicotinamide nucleotides showed that both content and state of reduction (mainly of NADPH) were lower in the marsupial mitochondria than in mice mitochondria despite the similarity in the activity of the glutathione peroxidase/reductase system. Overall, these data suggest that PTP opening is an important event in processes ofCa2+signalling to cell death mediated by mitochondrial redox imbalance inG. microtarsus.