The Involvement of Lipid Radical Cycles and the Adenine Nucleotide Translocator in Neurodegenerative Diseases

Abstract

The major cause of neurodegenerative disorders, including mid- to late-life onset Alzheimer's Disease, is permanent oxidative stress in the brain. Polyunsaturated fatty acids (PUFA) and α-tocopherol (α-TOH) are the most oxygen-sensitive constituents of cells. The presence of α-TOH in biological membranes is required but not sufficient to protect them against lipid peroxidation. The data presented in this review consider the role of α-TOH and cytochrome b₅ which permit operation of lipid-radical cycles and the participation of lipid-radical reactions in key processes occurring in the membrane. Analysis of role of these cycles in membrane bioenergetics led us to a model involving the adenine nucleotide translocator and ATP synthesis in brain mitochondria. This paper summarizes experimental evidence for oxidative and non-oxidative pathways of PUFA metabolism with respective intermediates, which could be relevant to elucidation of new mechanisms of neurodegenerative diseases. Lipid-radical reactions in membranes work as important component of normal cell metabolism. Discussion is focused on the consequences of ineffective electron transfer to peroxyl radicals (LOO˙→ LOO^-) and excessive oxidative pathway of PUFA metabolism (LOO˙→LOOH) with two reactive secondary products: malondialdehyde and methylglyoxal. Our future aim is to develop a more detailed model supplemented by the formation of lipofuscin and amyloid structures.