ИСТИНА

Regulation of the efficiency of oxidative phosphorylation is a key element in the functioning of mitochondria providing a reasonable balance between the synthesized ATP and the fraction of free energy of substrate oxidation released as heat. The share of generated chemical energy in the form of ATP directly depends on proton-motive force and consequently regulates the processes associated with this component, in particular the generation of reactive oxygen species (ROS). Sixty years ago, V.P.Skulachev presented his first proof of thermoregulatory uncoupling during short-term exposure to cold, for the first time proving the possibility of intrinsic regulation of oxidative phosphorylation responded to physiological needs. That time, the question of a possible endogenous uncoupler responsible for thermoregulatory uncoupling was resolved through the idea to consider fatty acids as this regulator. Later, the interaction of fatty acids and mitochondria took a significant part of the research in the Skulachev’s group. On the one hand, it seemed that the mechanism of uncoupling is easily explained by the formation of a shuttling proton transfer through the bilayer of the inner mitochondrial membrane, but after the detection of retardation of the protonophoric action of uncouplers by inhibiting the ATP/ADP translocator (ANT) or dicarboxylate carrier, this mechanism did not look trivial anymore, because a priori it undermined the involvement of some mitochondrial proteins in the mechanism of uncoupling, in particular ANT. By the way, this indirect evidence obtained in the 20th century by Russian scientists that fatty acids provide proton conductance through the ANT was confirmed in 2020 by American scientists. It becomes clear that by providing proton leak through mitochondrial proteins, fatty acids, and other possible physiological regulators can not only regulate ATP synthesis, but also finely regulate the synthesis of ROS, which are considered as physiological and pathogenic regulators of cellular activity. This relationship was shown in the same group of Russian scientists, with the key regulator of ROS synthesis being the membrane potential (∆Ψm) built over the inner mitochondrial membrane. It became clear that homeostasis of∆Ψm is one of the key components and indicators of mitochondrial Section 1 functional activity. Now, we can attribute to this factor a number of vital physiological intracellular functions, such as: to be an intermediate element of ATP synthesis, an element of the mitochondrial quality control mechanism, a control component of the transport of a number of proteins to the mitochondria, possible participation in antiviral and antibacterial defense, a driving force for the transport of cations, such as calcium, magnesium and especially potassium ions, which can provide potassium energetics, and the associated transport of water in and out of mitochondria. There are still a number of speculative assumptions about the role of ∆Ψm, but the use of drugs conjugated with permeable ions traveling to mitochondria driven by ∆Ψm is no longer speculative, but practically used in medical practice. Thus, the mitochondrial machine regulated by endogenous components can provide not only cellular homeostasis, but also it participates in wanted and unwanted cell death. In this process, an important role is played by ROS, the generation of which under special conditions inside the mitochondria can carry an avalanche character which was called ROS induced ROS release, and currently it considered as the fundamental basis of pathogenesis. In general, the strong shift from homeostasis of ∆Ψm, the levels of intracellular ATP and intracellular and intramitochondrial ROS being a result of improper functioning of the mitochondria is the basis of pathogenesis determined by the occurrence and course of diseases and aging. Supported by NSF grant #19-14-00173.