Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

Abstract

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.

Keywords: cardiovascular diseases; heart failure; mitochondria.

Figure 1.. Multiplicity of mitochondrial function.

Mitochondria are known as the powerhouse of the cell. In addition to generating ATP, intermediate metabolism in the mitochondria produces metabolites for biosynthesis, protein modification, and signal transduction. Oxidative phosphorylation regulates NAD(H) redox state and is coupled with the generation of reactive oxygen species (ROS), both can modulate and/or trigger post-translational modifications. Mitochondrial metabolism is stimulated by Ca²⁺ - lower Ca²⁺ level impairs mitochondrial activity while calcium overload can trigger the opening of the mitochondrial permeability transition pore (mPTP). The release of mitochondrial contents, such as cytochrome C, induces apoptosis, or the loss of membrane potential (a consequence of prolonged mPTP opening) causes ATP deprivation and necrosis. Leakage of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA and peptides, or excessive ROS generation can cause inflammation that results in further tissue damage. Mitochondrial function is also regulated by biogenesis, fission, and fusion dynamics, and protein quality control via mitophagy. The transition of mitochondria from a powerhouse to a death engine involves a shift of the entire spectrum of functions.

Figure 2:. Targeting Mitochondrial Functions in Heart, Lung, and Blood (HLB) Health and Disease.

Mitochondria in multiple cell and organ types contribute to the pathogenesis of heart failure or its risk factors. A better understanding of basic mitochondrial biology including the multiplicity of functions played by mitochondria, their role in intra- and inter-cellular communication, and the relationship between mitochondrial genotype and phenotype is a high priority in developing mitochondria-based therapy. Other priority areas emphasized the need for improved tools and/or the development of new approaches for the study of mitochondrial function in humans and the development of strategies for the translation of basic observations to the clinic.