The involvement of lipid radical cycles and the adenine nucleotide translocator in neurodegenerative diseases.
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 alpha-tocopherol (alpha-TOH) are the most oxygen-sensitive constituents of cells. The presence of alpha-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 alpha-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.
Dmitriev
L F
LF
Group of Neurobiology, Cardiology Research Center, Moscow, Russia. leon.d@mail.ru
D033741:Adenine Nucleotide Translocator 1 / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology; D015786:Cytochromes b5 / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D011765:Pyruvaldehyde; D024502:alpha-Tocopherol / Q000378:metabolism
D033741:Adenine Nucleotide Translocator 1; D005231:Fatty Acids, Unsaturated; D005609:Free Radicals; D011765:Pyruvaldehyde; D000255:Adenosine Triphosphate; D015786:Cytochromes b5; D024502:alpha-Tocopherol