Shortage of Lipid-radical Cycles in Membranes as a Possible Prime Cause of Energetic Failure in Aging and Alzheimer Disease

Abstract

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.

Fatty aldehyde dehydrogenase is up‐regulated by polyunsaturated fatty acid via peroxisome proliferator‐activated receptor α and suppresses polyunsaturated fatty acid‐induced endoplasmic reticulum stress

“…On the basis of previous results and those presented in the present study, we propose the following mechanism for the suppression of ER stress by FALDH-N. Excess linoleic acid is modified to fatty aldehydes by non-enzymatic lipid peroxidation [38]. The adduction of fatty aldehydes to proteins leads to dysfunction of the proteins [34] and the accumulation of abnormal proteins causes an ER stress response.…”

“…These proteins might induce excessive ER stress preceding apoptosis in neuronal cells that contain abundant various PUFAs, which are essential for the development and maintenance of the central nervous system. Therefore, a defense system against lipid peroxidation of oxygen‐sensitive PUFAs is important for the maintenance of neuronal cells [38,40]. To investigate the essential role of FALDH in protection against lipid peroxidation of PUFAs in the nervous system, further analyses using neuronal cells lacking FALDH are required.…”

Delineating the Role of Glutathione Peroxidase 4 in Protecting Cells Against Lipid Hydroperoxide Damage and in Alzheimer's Disease

“…(A, B) Stably transfected cells were cultured and the levels of the lipid peroxidation by-products, MDA or 4-HNE, measured as described in the Materials and Methods. In (A), 3Â10 6 cells=sample of both cell lines were analyzed by the MDA assay. *p < 0.01; NIH=siGPx4-3 was compared with NIH=pU6m3.…”

Lipid peroxidation in Alzheimer’s Disease: emphasis on metal-mediated neurotoxicity

“…Acyl-SG derivatives being potent analogs that can counter lipoperoxidation in primary fibroblasts from familial AD patients can become a substantial therapeutic option for AD and other oxidative stress-related diseases (43). However, vitamin E that plays a central role in protecting the membranes against lipid hydroperoxides formation when inadequate leads to energetic failure in aging and AD (46). Creatine kinase reversibly catalyzes the transfer of the high-energy phosphoryl group from phosphocreatine to magnesium adenosine diphosphate for rapid regeneration of ATP.…”

“…PUFA and alpha-tocopherol being the most oxygen-sensitive constituents of cells are expected to maintain homeostasis. However, vitamin E that plays a central role in protecting the membranes against lipid hydroperoxides formation when inadequate leads to energetic failure in aging and AD (46).…”