Shortage of lipid-radical cycles in membranes as a possible prime cause of energetic failure in aging and Alzheimer disease.

Polyunsaturated fatty acids (PUFA) and alpha-tocopherol (alpha-TOH) are the most oxygen-sensitive constituents of cells. alpha-TOH is a member of the vitamin E family that is considered the most important lipophilic antioxidant in cell membranes. Its importance is emphasized by the involvement of oxidative stress in injury to the central nervous system and neurodegenerative diseases. Currently, alpha-TOH transfer protein (TTP), is believed to play a significant role in maintaining the vitamin status but the presence of alpha-TOH in membranes is required but not sufficient to protect the membranes against lipid hydroperoxides (LOOH) formation. The lipid-radical theory presented in this review considers the role of two membrane factors--alpha-tocopherol and cytochrome b5; these factors secure the functioning of lipid-radical cycles and the participation of lipid-radical reactions in the key membrane processes. The prominent intermembrane reaction realized via a protein-lipid interaction, during which electron transport from cytochrome b5--located in the outer membrane--to peroxyl radical (LOO*)--located in inner membrane--causes reduction of the peroxyl radical: cyt.b5red + LOO* --> cyt.b5ox + LOO(-). This secures an interaction of alpha-TOH with other intermediate, LOO(- )excepting the LOOH formation. The discussion will be focused on the consequences of ineffective electron transfer to LOO* and excessive oxidative pathway of metabolism of the PUFA (LOO* --> LOOH). Assuming the operation of cytochrome b5/alpha-tocopherol-controlled lipid-radical cycles and considering the role of the cycles in membrane bioenergetics we arrive at a model for effective function of adenine nucleotide translocator and ATP synthesis in mitochondria. This paper summarizes our experimental evidence that the oxidative and non-oxidative pathways of metabolism of PUFA via their respective intermediates occur in the cells. While this fact is not widely appreciated it may be relevant to elucidation of new mechanisms of neurodegenerative diseases.