Inorganic polyphosphate (polyP) physiology Inorganic polyphosphate in cardiac myocytes: from bioenergetics to the permeability transition pore and cell survival

Abstract Inorganic polyphosphate (polyP) is a linear polymer of P i residues linked together by high-energy phosphoanhydride bonds as in ATP. PolyP is present in all living organisms ranging from bacteria to human and possibly even predating life of this planet. The length of polyP chain can vary from just a few phosphates to several thousand phosphate units long, depending on the organism and the tissue in which it is synthesized. PolyP was extensively studied in prokaryotes and unicellular eukaryotes by Kulaev's group in the Russian Academy of Sciences and by the Nobel Prize Laureate Arthur Kornberg at Stanford University. Recently, we reported that mitochondria of cardiac ventricular myocytes contain significant amounts (280 ± 60 pmol/mg of protein) of polyP with an average length of 25 P i and that polyP is involved in Ca 2 + -dependent activation of the mitochondrial permeability transition pore (mPTP). Enzymatic polyP depletion prevented Ca 2 + -induced mPTP opening during ischaemia; however, it did not affect reactive oxygen species (ROS)-mediated mPTP opening during reperfusion and even enhanced cell death in cardiac myocytes. We found that ROS generation was actually enhanced in polyP-depleted cells demonstrating that polyP protects cardiac myocytes against enhanced ROS formation. Furthermore, polyP concentration was dynamically changed during activation of the mitochondrial respiratory chain and stress conditions such as ischaemia/reperfusion (I/R) and heart failure (HF) indicating that polyP is required for the normal heart metabolism. This review discusses the current literature on the roles of polyP in cardiovascular health and disease

OPPORTUNITIES AND PROSPECTS OF DEVELOPMENT FOR THE DIGITAL ECONOMY IN THE WORLD AND THE RUSSIAN FEDERATION

Implementation of digital economy tools in the new information environment is a catalyst for innovative development of the economic environment of the state as a whole. It is obvious that not all the available opportunities and resources for the development of the digital economy have found their vectors of implementation, many of them have not been studied sufficiently and haphazardly, the existing potential and prospects have not been disclosed.Understanding of the need to develop elements of the digital economy has come to a head in the Russian economic and legal environment, as evidenced by the development and implementation of priority areas of the strategy of scientific and technological development of Russia. The mentioned problems determine the relevance of the research study of the possibilities of applying the positive foreign experience of digitalization of the economy in domestic practice. The paper provides an overview of the main categories of the digital economy, examines the features of its widespread distribution in the countries of the world, assesses the opportunities and prospects for the development of digitalization in Russia. New technologies, criteria and approaches to assessing the level of the digital economy, its institutionalization require effective regulation and management.

Perspectives for non-primary export development in Russia and measures of its tax incentives

Non-primary export is one of the most promising areas for the development of Russian foreign economic activity. However, the significant influence of geopolitical problems and underdeveloped internal mechanisms of statutory regulation, state support and stimulation of non-primary exports in Russia do not allow to use all available potential in this regard. As such, the problems of non-primary export development in Russia are being actualized with a view to ensuring a positive influence of this kind of foreign economic activity both on the welfare of the state as a whole and on strengthening its positions in world markets.The purpose of the article is to consider the specifics of non-primary export development in Russia and to propose measures to stimulate its growth.The object of the study is the existing system of non-primary export in Russia with its inherent features and operating principles.The research methodology is as follows: scientific search, generalization, systematization, analysis, graphical construction, modeling, formalization, and forecasting.The key research results consist in the systematization of information on Russia’s promising non-primary export industries, the study of the current system of state support for export, the identification of problematic aspects and the search for solutions, and the development and justification of mechanisms for tax incentives for non-primary export, including due to the proposed division of enterprises into target groups depending on the volume of income from their foreign economic activities.The practical value of the results obtained is that they can be used at the macro level by introducing amendments to the regulatory and legislative acts of the Russian Federation on export regulation in accordance with the results of the grant of the President of the Russian Federation for stimulating and supporting non-primary export

Cardiac-specific Conditional Knockout of the 18-kDa Mitochondrial Translocator Protein Protects from Pressure Overload Induced Heart Failure.

Heart failure (HF) is characterized by abnormal mitochondrial calcium (Ca2+) handling, energy failure and impaired mitophagy resulting in contractile dysfunction and myocyte death. We have previously shown that the 18-kDa mitochondrial translocator protein of the outer mitochondrial membrane (TSPO) can modulate mitochondrial Ca2+ uptake. Experiments were designed to test the role of the TSPO in a murine pressure-overload model of HF induced by transverse aortic constriction (TAC). Conditional, cardiac-specific TSPO knockout (KO) mice were generated using the Cre-loxP system. TSPO-KO and wild-type (WT) mice underwent TAC for 8 weeks. TAC-induced HF significantly increased TSPO expression in WT mice, associated with a marked reduction in systolic function, mitochondrial Ca2+ uptake, complex I activity and energetics. In contrast, TSPO-KO mice undergoing TAC had preserved ejection fraction, and exhibited fewer clinical signs of HF and fibrosis. Mitochondrial Ca2+ uptake and energetics were restored in TSPO KO mice, associated with decreased ROS, improved complex I activity and preserved mitophagy. Thus, HF increases TSPO expression, while preventing this increase limits the progression of HF, preserves ATP production and decreases oxidative stress, thereby preventing metabolic failure. These findings suggest that pharmacological interventions directed at TSPO may provide novel therapeutics to prevent or treat HF

Value formation of innovative product : a way to commercialization

Purpose: The issues of studying the value formation process of an innovative product, from the idea to the prototype to the commercialization of the output from the production line, depending on the type of innovations, are the aims of this article. Design/Methodology/Approach: The conceptual framework of "value" and "innovations" is explored and the theoretical basis of the value approach is revealed at the beginning of the article. The definition of an innovative product is given and the development process and the mechanism of its value formation at each development phase are revealed. Findings: The value-added elements are specified, from the idea generation to the commercialization of the innovative product. The expenses for the calculation items and the development phases of the innovative product are estimated. Practical Implications: Categories of the innovation-based economy development, as "innovation", "innovative product", and "value" are not sufficiently studied. Intensive discussions are taking place in the scientific community regarding what an innovative product is and how its value is formed. A specific result of intellectual activity, at the initial stage of its formation represents an idea that is difficult to be estimated. Originality/Value: The problematics for further research of value formation of innovative products depending on their specific nature is put.The article was prepared in the course of carrying out research work within the framework of the project part of the state task in the field of scientific activity in accordance with the task No. 26.2758.2017 / PCh (26.2758.2017 / 4.6) for 2017-2019 on the topic "System for the formation and distribution analysis of the value of innovative products based on the infrastructure concept".peer-reviewe

Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes

Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP$_3$) by activating their membrane-bound receptors. We have previously demonstrated that IP$_3$-mediated sarcoplasmic reticulum (SR) Ca$^{2+}$ release results in mitochondrial Ca$^{2+}$ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP$_3$-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca$^{2+}$ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca$^{2+}$ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca$^{2+}$ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca$^{2+}$ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca$^{2+}$ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca$^{2+}$ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP$_3$-mediated SR Ca$^{2+}$ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP$_3$R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter)

Mitofusin 2 is essential for IP3-mediated SR/mitochondria metabolic feedback in ventricular myocytes

Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP$_3$) by activating their membrane-bound receptors. We have previously demonstrated that IP$_3$-mediated sarcoplasmic reticulum (SR) Ca$^{2+}$ release results in mitochondrial Ca$^{2+}$ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP$_3$-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca$^{2+}$ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca$^{2+}$ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca$^{2+}$ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca$^{2+}$ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca$^{2+}$ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca$^{2+}$ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP$_3$-mediated SR Ca$^{2+}$ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP$_3$R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter)