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Early Changes in Intramitochondrial Cardiolipin Distribution during Apoptosis¹

Department of Human Physiology, University of Malaga, Campus Teatinos, 29080 Malaga, Spain [M. G. F.]; Department of Biomedical Sciences, Section of General Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy [M. G. F., L. T., L. M., M. N., M. P., A. C.]; Department of Experimental Pathology, Section of Microbiology, University of Bologna, 40126 Bologna, Italy [S. S.]; and Laboratory of Confocal Microscopy and Image Analysis, Department of Biophysics, Jagiellonian University, 30-387 Krakow, Poland [J. D.]

Cardiolipin (CL) is essential for the functionality of several mitochondrial proteins. Its distribution between the inner and outer leaflet of the mitochondrial internal membrane is crucial for ATP synthesis. We have investigated alterations in CL distribution during the early phases of apoptosis. Using two classical models (staurosporine-treated HL-60 cells and tumor necrosis factor -treated U937 cells), we found that in apoptotic cells CL moves to the outer leaflet of mitochondrial inner membrane in a time-dependent manner. This occurs before the appearance of apoptosis markers such as plasma-membrane exposure of phosphatidylserine, changes in mitochondrial membrane potential, DNA fragmentation, but after the production of reactive oxygen species. The exposure of a phospholipid on the outer surface during apoptosis thus occurs not only at the plasma membrane level but also in mitochondria, reinforcing the hypothesis of mitoptosis as a crucial regulating system for programmed cell death, also occurring in cancer cells after treatment with antineoplastic agents.

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