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Decrease in ATP biosynthesis and dysfunction of biological membranes. Two possible key mechanisms of phenoptosis

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Abstract

Metabolic syndrome is extremely prevalent in the world and can be considered as one of main factors leading to accelerated aging and premature death. This syndrome may be closely linked with age-related disruptions in hypothalamic-pituitary system function, which perhaps represent a trigger mechanism of development of endocrine and cardiovascular pathologies. Age-related elevation of the sensitivity threshold of the hypothalamus to regulatory signals in association with low mobility and excessive diet trigger a cascade of biochemical reactions that might be used for activation of programmed death of the organism — phenoptosis. Accumulation of fatty acids in a cell and resulting lipotoxicity include resistance to insulin and leptin, endoplasmic reticulum stress, uncoupling of oxidation and phosphorylation, and dysfunction of biological membranes. Decrease in ATP synthesis is correlated with accumulation of calcium ions in cells, dysfunction of mitochondria, and increasing apoptotic activity. Age-related activation of mTOR (which is greatly influenced by excess energy substrates) has deleterious impact on one of the main mechanisms of cell defense by which defective mitochondria are replaced: mitophagy and biogenesis of mitochondria will be suppressed, and this will increase in greater degree mitochondrial dysfunction and oxidative stress. Fatty acid-induced inflammation will increase activity of nuclear factor NF-κB, the well-known stimulator of age-related pathologies. The final stage of phenoptosis can be represented by endothelium dysfunction related with oxidative stress, insulin resistance, and the most prevalent cardiovascular pathologies.

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Abbreviations

ER:

endoplasmic reticulum

FAs:

fatty acids

FFAs:

free fatty acids

LPO:

lipid peroxidation

PL:

phospholipid

ROS:

reactive oxygen species

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  1. Center for Rehabilitation Medicine, ul. Mechnikova 8, 49000, Dnepropetrovsk, Ukraine

    A. V. Rzheshevsky

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Original Russian Text © A. V. Rzheshevsky, 2014, published in Biokhimiya, 2014, Vol. 79, No. 10, pp. 1300–1315.

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Rzheshevsky, A.V. Decrease in ATP biosynthesis and dysfunction of biological membranes. Two possible key mechanisms of phenoptosis. Biochemistry Moscow 79, 1056–1068 (2014). https://doi.org/10.1134/S0006297914100071

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