HEART FAILURE IN HUMANS: MITOCHONDRIAL STRUCTURE AND FUNCTION

Аннотация

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria- endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promisingclinical mitochondrial targets for heart failure. Keywords:cardiovascular diseases, heart failure, hypertension, mitochondria, myocardium Cardiovascular diseases (CVDs), which affect blood vessels or the heart, are the leading cause of death globally, accounting for % of US deaths. Although CVD generally affects the left ventricle, the right ventricle plays a crucial role in cardiovascular diseases, including pulmonary hypertension. Other forms of heart disease include valvular heart disease, cardiomyopathy, and arrhythmias. The most common form of heart disease is coronary artery disease, which results from the buildup of plaque in the arteries that supply blood to the heart. Coronary artery disease leads to chest pain, heart attacks, and heart failure (HF),– which is defined by the American Heart Association as a condition in which theheart pumps insufficient blood to meet the body’s needs. HF, which presents clinically with or without preserved ejection fraction and is the result of cardiomyocyte injury, is characterized by the inability of the heart to fill and expel blood from the left ventricle effectively., Injury to the myocardium can result from hypertension, diabetes, and coronary artery disease. Various types of HF present with different symptoms that can include shortness of breath, fatigue, congestion, and peripheral edema It is important to understand the molecular bases of the various types of HF. CVD increases with age, as does mitochondrial dysfunction. Many lines of evidence from animal models and human studies implicate mitochondrial DNA (mtDNA) heteroplasmy and mitochondrial biogenesis impairment occurring before and during early HF, suggesting mitochondrial dysfunction is an early hallmark of HF and a potential therapeutic target in CVD., Reviews 98,7:ROTCAFTCAPMI .SECNEICSLACIDEM ,5202, enuJ,5emuloV gro.srehsilbupcimedaca.www that consider mitochondria for the treatment of HF– have focused on mitochondrial dynamics or function. The multifaceted regulation of mitochondrial structure and function is poorly understood, especially in the context of age-dependent HF. Tools that allow for this understanding have only been developed and become more widely available within the last years. For example, focus ion-beam scanning electron microscopy (SEM), serial block face SEM, and correlative light electron microscopy, have all undergone significant improvements, which have allowed for -dimensional (D) structures of organelles including mitochondria to be better interrogated in heart development and failure. D tomography has also been used to perform morphological analysis of cardiac mitochondria to provide greater insights into ultrastructural changes. Concurrent advances in cryo-electron microscopy have enabled the resolution of the mitochondrial oxidative phosphorylation machinery, such as the mitochondrial supercomplex IIIIIV. Outside of microscopy, proteome, and acetylome analyses have accelerated, which have allowed researchers to glean the functional role of specific acetylation sites. The study of in vivo freshly excised hearts has used high- resolution respirometry to study respiratory function,while mechanistic studies have continued to be guided by broader advancements such as those in CRISPR/Cas. Together, thesetechnologies havecontinued to bolsterour understanding of mitochondria. Mitochondria are central to many of the signaling cascades involved in HF (reviewed by He et al). Here, we highlight recent developments and important future directions in the field, including the potential role of mitoch