Regulatory lipidomics in cytochrome c-dependent mechanisms of cell death. The role of phosphatidic acid and hydroperoxides in the initiation and switching from pro-apoptotic processes to pro-ferroptotic reactions

Abstract

Regulatory lipidomics is one of the most discussed topics affecting cytochrome c-dependent mechanisms of cell death. Phosphatidylethanolamine regulates ferroptosis, phosphatidylserine stimulates phagocytosis, and cardiolipin is a key phospholipid in the development of apoptosis. However, we have previously shown that phosphatidic acid can also enhance the binding of cytochrome c to the membrane. This binding leads to a change in the conformation of cytochrome c and, as a result, leads to an increase in its peroxidase activity and intensification of lipid peroxidation. Additionally, we showed that hydrogen peroxide or lipid hydroperoxides, after being to “pro-apoptotic” cytochrome c complexes with phosphatidic acid, accelerate the heme iron release. This iron can serve as an initiator of ferroptotic processes, and the porphyrin remaining in the membrane after laser irradiation promotes the formation of singlet oxygen, followed by the generation of new lipid hydroperoxides in biological membranes. Thus, the role of phosphatidic acid in the development of pro-apoptotic cytochrome c-dependent molecular processes is demonstrated. It has also been shown that hydroperoxides mediate disruption of the cytochrome c heme, which can switch pro-apoptotic processes to pro-ferroptotic reactions.

Speaker

German O. Stepanov
Department of General and Medical Biophysics, Institute of Biomedicine, N.I. Pirogov Russian National Research Medical University
Russia

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