Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials

Abstract

Mitochondrial dysfunction is considered as a crucial contributory factor in cardiac pathology. This has highlighted the therapeutic potential of targeting mitochondria to prevent or treat cardiac disease. Mitochondrial dysfunction is associated with aberrant electron transport chain activity, reduced ATP production, an abnormal shift in metabolic substrates, ROS overproduction and impaired mitochondrial dynamics. This review will cover the mitochondrial functions and how they are altered in various disease conditions. Furthermore, the mechanisms that lead to mitochondrial defects and the protective mechanisms that prevent mitochondrial damage will be discussed. Finally, potential mitochondrial targets for novel therapeutic intervention will be explored. We will highlight the development of small molecules that target mitochondria from different perspectives and their current progress in clinical trials. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

Figure 1

The main mitochondrial function is energy production. Mitochondria transform different substrates into ATP by driving the TCA cycle that supplies electron carriers. The electron carriers, NADH and FADH₂ then stimulate the ETC to maintain a constant flux of protons towards the intermembrane space. The gradient generated by this flux is the force that powers ATP synthase. Mitochondrial substrates do not enter directly into the TCA cycle. Fatty acids and ketones are oxidized inside the mitochondria and broken into acetyl‐CoA. Glucose and lactate are converted into pyruvate in the cytosol, and pyruvate is converted into acetyl‐CoA in the mitochondrial matrix. Amino acids can supply not only acetyl‐CoA but also other TCA intermediates.

Figure 2

Mitochondrial dysregulation under pathological stresses. Sustained pathological stresses result in alterations in mitochondrial structure and function through different mechanisms, eventually leading to cardiac pathological remodelling and heart failure. Firstly, aberrant metabolic substrate preference in the heart impairs oxidative phosphorylation and ATP production, resulting in energy insufficiency. Secondly, an imbalance between mitochondrial fission and fusion induces the accumulation of fragmented mitochondria and impaired mitochondrial quality control, which ultimately disrupts the mitochondrial network and functions. Thirdly, excessive ROS production, increased mtDNA damages, activated cell death pathways and mPTP opening are the main causes of cell death. Finally, a dysregulation of transcription factors and abnormal posttranslational modification of mitochondrial function‐related genes impairs mitochondrial biogenesis.

Figure 3

Preserving mitochondrial biogenesis and function as therapeutic approaches in cardiac diseases. The potential therapeutic strategies aim to facilitate mitochondrial biogenesis and maintain mitochondrial function to prevent cardiac dysfunction, including (i) enhancing mitochondrial biogenesis; (ii) retaining mitochondrial metabolism by limiting fatty acid import and oxidation while improving glucose utilization; (iii) reducing ROS production by ROS scavengers; and (iv) inhibiting mPTP by the use of mPTP inhibitors.