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.

In 1961, Peter Mitchell advanced a new idea for solving the problem of coupling between oxidation and phosphorylation, but some aspects of the relationship between the redox-chain as a potential energy donor and different energy acceptors remain largely unknown. The main structure-function relationships behind catalytic rate optimization in membrane enzymes are highly important, and comparative analyses of the energetics of catalytic reactions from membrane proteins of different destination are needed to advance our understanding. Moreover, the mode of control of primary radicals, such as reactive oxygen species (ROS), should be considered. For example, iron is essential for most organisms because it serves as an electron donor and acceptor in various metabolic processes. However, these chemical properties also allow iron to participate in the formation of ROS that cause substantial damage to lipids; iron can contribute to excess production of damaging ROS through Fenton chemistry. The evidence that iron contributes to various diseases of ageing is to be examined along with the need for low or moderate levels of iron, depending on homeostasis level. If this level in the organs and tissues is close to the optimal amount needed for an initiation of lipid-radical cycles, which may be responsible for the effectiveness of some membrane enzymes, this might minimize the ROS production and retard the processes related to ageing. To my mind, biological membranes possess an internal heat and imaginary temperature that are new, unique physiological parameters related to a role as factors of biological catalysis. This is speculation and additional studies will be needed to determine whether the imaginary temperature has an equal importance with the real temperature in cellular metabolism, membrane energetics (microsomal monooxygenase and ATP synthesis) and ageing.