Focus on Mitochondria Dysfunction and Dysregulation in Heart Failure: Towards New Therapeutic Strategies to Improve Heart Function

Abstract

Mitochondria have a central role in normal cardiac muscle function. To sustain electrical and mechanical activities, the heart on average needs to synthesis anywhere from 6 kg to 30 kg of adenosine triphosphate (ATP) per day.^1–4 To meet most of this demand, the heart relies on the oxidation of fatty acids and to a lesser extent glucose by mitochondria. The importance of mitochondria to normal cardiac function is underscored by the fact that these organelles comprise some 30% of the volume of the cardiac muscle.⁴ Given their prominent role in heart muscle, it is not surprising that mitochondria have also been implicated in key aspects of heart failure (HF), such as apoptosis, oxidative stress, and calcium dysfunction. HF is also associated with alterations in the metabolic profile of the heart consistent with insufficient and inefficient mitochondrial respiration.^1–4 Studies of global changes in metabolism associated with HF have confirmed alterations consistent with this pathology, such as decreased fatty acid oxidation with advanced HF. To date, these findings have been too broad or variable to translate into effective therapies; however, new technologies that allow us to explore in great detail the expression profile and structural modifications of proteins within mitochondria of the failing heart, along with a revolutionary understanding of mitochondrial dynamics, have sparked renewed interest in research into the role and possible therapeutic targeting of mitochondria in HF. In this issue, we present 3 review articles that deal with different and topical aspects of this topic.

Rather than being “static factories producing energy,” mitochondria are now known to be dynamic organelles that undergo regulated fission (division) and fusion. As discussed by Chen and Knowlton,⁵ under normal conditions, fission and fusion occur with equal frequency. An imbalance in one or both, such as increased fission and/or decreased fusion, can lead to apoptosis, a process that contributes to myocyte loss in HF. Intriguingly, the fission-fusion interplay appears to be essential for optimal mitochondrial energetics and function, although the basis for this is not known. Regulated fission and fusion are likely important as well for mitochondrial quality control, allowing for the selection of damaged or dysfunctional mitochondria prior to autography.^1,6,7 Whether the mitochondrial fission-fusion asymmetry is a cause or consequence of HF is not established. In any event, these new insights into mitochondrial dynamics bring new significance to older observations of gross changes in mitochondria size, shape, and number with cardiomyopothies and HF. They further suggest the possibility of new therapeutic avenues to restrain the progression of or even reverse HF.

In their contribution, Hollander and colleagues⁸ discuss changes in the expression levels of all of the mitochondrial proteins that occur in HF. This is a new area of investigation that could help identify new biomarkers of disease progression. The functional significance of many of the changes is yet to be understood. Nonetheless, several intriguing observations have emerged, including the fact that the expression of proteins involved in substrate-specific utilization and oxidative stress/protection is impacted by HF. In addition, the protein profile of the inner mitochondrial membrane, which functions in respiration and energy production, seems especially susceptible to alterations in HF. Understanding the basis for this greater susceptibility may lead to innovative ways to treat or prevent HF. Of note, others recently reported that the individual activities of the electron transport chain complexes were normal in a canine coronary microembolization-induced model of moderately severe HF; however, levels of the major form of “respirasome,” which is critical for oxidative phosphorylation, ie, the supercomplex consisting of complex I/complex III dimer/complex IV, were decreased.⁹ Proteomic profiling may provide insights into what negatively impacts the assemblage of the respiratory complexes into higher-order complexes required for mitochondrial respiration.

Finally, O’Rourke and colleagues¹⁰ discuss the regulation of mitochondrial function by posttranslational modifications of proteins, in particular phosphorylation, and its potential significance in HF. This burgeoning area of research is fueled by new mass spectrometry-based technologies. As the authors discuss, the findings thus far raise several questions, including the impact that specific protein phosphorylation sites have on metabolic flux and details on the organization and regulation of kinase-phophatase networks within the mitochondria. Answers may provide new ways to treat HF. For instance, evidence was recently reported that the decreased assemblage of respirasomes in the canine coronary microembolization-induced HF model was associated with protein kinase A–mediated phosphorylation of specific complex IV subunits.¹¹ This phosphorylation may be responsible for reducing respirasome stability or preventing their formation, so that therapies targeting this phosphorylation event might enhance mitochondrial respiration in HF.

Other protein posttranslational modifications assuredly have significance for HF as well, including those that are redox-related. HF is associated with oxidative stress and increased formation of reactive oxygen species (ROS).¹² Under these conditions, protein tihols may undergo reversible modifications including S-glutathionylation and subsequent disulfide bind formation that negatively impacts enzymatic function.¹³ Mitochondria are not only a source of ROS in HF, but are undoubtedly targets of ROS as well. Reduced mitochondrial ATP synthase activity in a canine dyssynchronous HF model was recently linked to S-gluathionylation of a cysteine residue within the α subunit that is critical for ATP synthase function, as well as increased disulfide bond formation in the α subunit.¹⁴ These posttranslational modifications were reversed by cardiac resynchronization therapy, which was associated with increased nitrosation of the ATP synthase α subunit. Thus, nitrosation driven by nitric oxide (NO) might serve as a posttranslational mechanism to enhance ATP synthase activity. HF may be associated with an effective decrease in levels of cardiac NO due to increased ROS formation.¹² Thus, increased ROS and decreased NO may together contribute to decreased mitochondrial ATP production in HF.

HF is a progressive disease with no true cure and a leading cause of death worldwide. Oxidative stress and metabolic disturbances contribute to the progression of HF. Given their key importance as producers of ATP and sources of ROS, mitochondria would seem to be obvious targets for novel therapeutics to treat HF. New technologies that allow us to look at mitochondrial protein expression and modifications, as well as mitochondrial dynamics (behavior), will hopefully lead towards that goal.