Recently we have found that the formation of megamitochondria in culture cells of various sources, induced by chemicals capable of generating free radicals, is followed by apoptotic changes of the cell. Detailed analysis on functional and morphological aspects of megamitochondria has enabled us to speculate that the formation of megamitochondria may be a prerequisite for free radical-mediated apoptosis: free radicals modify the mitochondrial membranes resulting in the fusion of adjacent mitochondria (megamitochondria formation). If the intracellular level of free radicals is continuously kept high, the permeability transition pores of the megamitochondria membranes are opened and megamitochondria become swollen. Oxygen consumption and the ability to synthesise ATP by swollen megamitochondria decrease distinctly. At the same time, cytochrome c is released from swollen megamitochondria into the cytoplasm. If lowered rates of the generation of reactive oxygen species from swollen megamitochondria, possibly due to decrease in their oxygen consumption, are effective enough to lower the intracellular level of free radicals, megamitochondria may return to normal. If not, decrease in the membrane potential of megamitochondria membranes causes the release of apoptosis-inducing factor into the cytoplasm. Cytochrome c and apoptosis-inducing factor thus released into the cytoplasm may cause cytoplasmic and nuclear apoptotic changes. Experimental data to support this hypothesis are presented.
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