Study of mitochondria in cardiomyocytes and nephrons of rats during the development of chronic hypertension

Annotation

Hypertension is one of the most common diseases in the world. The heart and kidneys are key target organs involved in and most affected by hypertension. These organs contain the most mitochondria and consume the most oxygen. A number of works have demonstrated the role of mitochondrial membrane potential mismatch in the development of cardio- and nephropathies. The membrane potential is finely regulated depending on the cellular needs. One of the important mechanisms of this regulation is the conformational rearrangements of electron carriers in the respiratory chain of mitochondria, in particular, cytochrome C, which is the only water-soluble mobile electron carrier. This project is aimed at studying the conformation of cytochrome C heme in intact functioning mitochondria of rat cardiomyocytes and nephrons at different stages of hypertension development. Surface-enhanced Raman spectroscopy (SERS) is a unique method that allows non-invasive study of conformational changes in heme of cytochrome C. In the course of the project, a comprehensive analysis of changes in the functioning of mitochondria during the development of hypertension is carried out: the conformation of the cytochrome C heme, the activity of individual respiratory complexes, the inner mitochondrial membrane potential, the ultrastructure of mitochondria, the level of oxidative stress. In addition, the project aims to study the state of the submembrane hemoglobin fraction in erythrocytes and the relationship between conformational changes in cytochrome C heme in cardiomyocytes and nephrons and hemoglobin heme in erythrocytes. The latter may become the basis for the development of sensitive SERS-sensors for predicting cardio and nephropathies by blood analysis.

Expected results

(1) Revealing the role of cytochrome C heme conformation in the regulation of mitochondrial activity in cardiomyocytes and nephrons as a fundamental problem. Cytochrome C is an obligate component of mitochondrial ETC and a key factor in the apoptosis initiation. Currently, data are beginning to appear on the role of cytochrome C as a regulator of electron transport in the electron transport chain (ETC); however, the mechanisms of this regulation are still poorly understood. By using SERS spectroscopy to study intact functioning mitochondria, we can study in more detail the relationship of conformational changes in cytochrome C heme with the ETC activity and the generation of membrane potential. (2) Identification of fundamental changes in the mitochondria of key target organs (heart, kidneys) at different stages of hypertension development may become the basis for the development of targeted therapy. Hypertension of any genesis in the absence of treatment leads to cardio- and nephropathies. Mitochondria play an important role in such organ damage. In the course of the project, we will study various aspects of mitochondrial functioning: the membrane potential, mitochondria morphology, the functioning of individual ETC complexes, the conformation of the cytochrome C heme - and we will reveal which properties of mitochondria change with the development of hypertension. We will identify the most sensitive lesions in mitochondria caused by hypertension, which could become potential targets for the development of therapy. (3) Revealing the relationship between the state of blood hemoglobin and the state of mitochondria in tissues will allow future developing a test system for determining pathologies in the mitochondria of organs by erythrocytes in the blood. Thus, we assume that our research will allow a deeper understanding of the molecular nature of damage to the heart and kidney during the development of hypertension and, in the future, may become the basis of new targeted therapy for cardio- and nephropathies. We believe that our methodological approaches will help to develop screening systems for early detection of cardiac and kidney pathologies and prognosis of the course of the disease.