Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association

Abstract

Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.

Keywords: AHA Scientific Statements; calcium; cardiovascular disease; cell death; energetics; metabolism; mitochondria; reactive oxygen species.

Figure 1.

Mutations in mitochondrial proteins (either from mutation in mitochondrial DNA or nuclear DNA) or acquired defects can lead to defects in mitochondrial quality control which leads to a vicious cycle of more acquired mitochondrial defects and defects in metabolic signaling, bioenergetics, calcium transport, ROS generation and activation of cell death pathways. This leads to a vicious feed-forward cycle leading to cardiomyocyte cell death.

Figure 2:

Bioenergetic paradigm for degenerative and metabolic diseases, cancer, and aging. Mitochondrial OXPHOS can be perturbed by nDNA genetic alterations and/or epigenomic regulation, by mtDNA ancient adaptive of recent deleterious mutations, or by variation in the availability of calories and in caloric demands. Alterations in mitochondrial structure and function can impair OXPHOS, which in turn can reduce energy production, alter cellular redox state, increase ROS production, deregulate Ca²⁺ homeostasis, and ultimately activate the mtPTP, leading to apoptosis. These and other consequences of OXPHOS perturbation can destabilize mtDNA. This results in progressive accumulation of somatic mtDNA mutations and decline of mitochondrial function, which accounts for aging and the delayed-onset and progressive course of degenerative diseases. As energy output declines, the most energetic tissues are preferentially affected, resulting in degenerative diseases of the heart, muscle, nervous system, and kidney. Aberrant mitochondrial caloric metabolism also leads to metabolic deregulation, endocrine dysfunction, and symptoms such as diabetes, obesity, and cardiovascular disease. Energetic failure of apoptosis can result in the release into the blood stream of mitochondrial antigenic cardiolipin, N-formylmethionine polypeptides, and mtDNA (mitochondrial damage associated molecular patterns (DAMPs) [311, 314, 361, 362]) can initiate the inflammatory response, contributing to autoimmune diseases (e.g., multiple sclerosis and type I diabetes) and possibly also to the inflammatory component of late-onset degenerative diseases. Finally, cancer cells must manage energy resources to permit rapid replication. Figure from [2].