Mitochondrial aspects of atherogenesis

Resident immune cells (monocytes) differentiate into macrophages M1-Mφ type in subendothelial space. The last ones initiate inflammatory response. Mitochondria in M1-Mφ macrophages not only release specific pro-inflammatory proteins, but first of all acidify phagosome environment by hydrogen cations (H+) and reactive oxygen species (ROS) as quickly as possible. They also increase heat production that contributes to the most efficient phagocytosis of pathogens. In this case, mitochondrial network is split into many small isolated fragments (fission) that maximizes the outer membrane area (by 10—15 times) and, accordingly, increases heat transfer rate. Stay of mitochondria M1-Mφ in this thermodynamic mode for a long time promotes accumulation of lipids with subsequent transformation into foam cells. Chronic imbalance in release of hydrogen cations (H+) and ROS occurs gradually in M1-Mφ. Their concentrations finally exceed the level allowed by functionality backlash that further potentiates inflammation, mtDNA damage and hyperlipidemia with final formation of CaP salts. Mitochondria life cycle is considered from the standpoint of thermodynamic and electrochemical oscillations. Four functional states with 2 reverse transitions are identified. These transitions are accompanied by changes of electron movement speed in respiratory chain inside the inner membrane according to direction of thermal potential. Mitochondrial biogenesis involves cycles of fission and fusion corresponding to two reverse transitions in thermodynamic and electrochemical cycles. When mitochondrial architectonics is disintegrated (the 1st reverse transition), inactive small defective organelles overloaded with amorphous CaP appear and undergo mitophagy. Active mobile fragments are combined into a tubular network structure (the 2nd reverse transition) to form a mitochondrial complex optimizing respiratory chain of oxidative phosphorylation and ATP release rate. In the context of atherosclerosis, mitophagy can reduce inflammatory response caused by M1-Mφ and degradation of endothelial cells. However, loss of metabolic flexibility of dissimilation process disturbs completion of mitophagy. This leads to overflow of cells with degraded organelles which are overloaded with CaP agglomerates.