Studies elucidating the mechanisms of calcium induced mitochondrial depolarization in individual isolated brain mitochondria

Among other mitochondrial functions, energy production and Ca2+ uptake are crucial for maintaining neuronal viability. Both of these functions are critically dependent on mitochondrial membrane potential (ΔΨm). Mitochondrial Ca2+ overload causing a dissipation of ΔΨm is a key component of several neuronal pathologies. However, the mechanism of Ca2+-induced depolarization in neuronal mitochondria remains unclear. Typically, ΔΨm has been evaluated as a single overall estimate from all mitochondria present in a given cell or tissue. However, recent data showed that the population of mitochondria isolated from tissues is not homogeneous, and averaged parameters from the whole population do not necessarily reflect the processes taking place in a single organelle. This review summarizes our recent studies of Ca2+-induced depolarization in individual mitochondria isolated from rat forebrain and immobilized to coverslips. Fluorescence imaging techniques and potentiometric fluorescent dyes were effectively used to study ΔΨm changes. The data have shown that Ca2+ triggers ΔΨm oscillations in brain mitochondria followed by a complete depolarization. Further investigation of this phenomenon led us to suggest that Ca2+-induced ΔΨm oscillations can represent an intermediate unstable state that may lead to irreversible mitochondrial dysfunction. Therefore, further study of this phenomenon would help to understand what causes the irreversible damage of mitochondria during cytosolic/mitochondrial Ca2+ overload. Here we discuss the effects of different modulators of the mitochondrial permeability transition pore on Ca2+-induced depolarization in brain mitochondria and in liver mitochondria, where the mechanism of Ca2+-depolarization is better understood. A comparison of these effects in brain and liver mitochondria led us to conclude that Ca2+ can induce reversible “low conductance” permeability transition in brain mitochondria, the phenomenon which requires a transient conformational change of the adenine nucleotide translocator from a specific transporter to a non-specific pore.