Commentary: Mitochondrial respiration in right heart failure

Abstract

Central MessageMitochondrial respiration is depressed in right heart failure and directly correlates with the severity of myocardial dysfunction.See Article page 129. Mitochondrial respiration is depressed in right heart failure and directly correlates with the severity of myocardial dysfunction. See Article page 129. Right ventricular (RV) dysfunction secondary to pulmonary hypertension is responsible for heart failure and death in many clinical settings, including congenital heart disease, chronic thromboembolic pulmonary hypertension, left-sided heart failure, and pulmonary artery hypertension.1Haddad F. Doyle R. Murphy D.J. Hunt S.A. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure.Circulation. 2008; 117: 1717-1731Crossref PubMed Scopus (948) Google Scholar Increase in RV afterload leads to a series of complex changes that initially result in compensatory hypertrophy and increased contractility, followed by RV dilatation and failure.2Vonk-Noordegraaf A. Haddad F. Chin K.M. Forfia P.R. Kawut S.M. Lumens J. et al.Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.J Am Coll Cardiol. 2013; 62: D22-D33Crossref PubMed Scopus (652) Google Scholar, 3Westerhof B.E. Saouti N. van der Laarse W.J. Westerhof N. Vonk Noordegraaf A. Treatment strategies for the right heart in pulmonary hypertension.Cardiovasc Res. 2017; 113: 1465-1473Crossref PubMed Scopus (43) Google Scholar The mechanisms responsible for these changes include ventriculoarterial uncoupling, myocardial ischemia secondary to decreased perfusion pressure and capillary rarefaction, inflammation, and fibrosis.3Westerhof B.E. Saouti N. van der Laarse W.J. Westerhof N. Vonk Noordegraaf A. Treatment strategies for the right heart in pulmonary hypertension.Cardiovasc Res. 2017; 113: 1465-1473Crossref PubMed Scopus (43) Google Scholar, 4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar Mitochondrial and bioenergetic alterations play a central role on the mechanisms that lead to RV failure.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar, 6Chan S.Y. Rubin L.J. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.Eur Respir Rev. 2017; 26 (Erratum in: Eur Respir Rev. 2018;27(147))Crossref PubMed Scopus (40) Google Scholar Although fatty acid oxidation generates most of the myocardial energy, aerobic glucose oxidation produces as much as 48% of the energy used by the RV.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar Several changes in myocardial bioenergetics occur during the development of RV failure secondary to pressure overload. There is a shift form glucose oxidation to anaerobic glycolysis (Warburg effect) with increased lactate production and intracellular acidosis. The changes in glucose oxidation are compensated by an increase in fatty acid oxidation (Randall effect) and glutaminolysis.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar, 6Chan S.Y. Rubin L.J. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.Eur Respir Rev. 2017; 26 (Erratum in: Eur Respir Rev. 2018;27(147))Crossref PubMed Scopus (40) Google Scholar, 7Freund-Michel V. Khoyrattee N. Savineau J.P. Muller B. Guibert C. Mitochondria: roles in pulmonary hypertension.Int J Biochem Cell Biol. 2014; 55: 93-97Crossref PubMed Scopus (38) Google Scholar These metabolic changes lead to mitochondrial hyperpolarization, decreased adenosine triphosphate production, and impaired myocardial contractility.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar, 6Chan S.Y. Rubin L.J. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.Eur Respir Rev. 2017; 26 (Erratum in: Eur Respir Rev. 2018;27(147))Crossref PubMed Scopus (40) Google Scholar, 7Freund-Michel V. Khoyrattee N. Savineau J.P. Muller B. Guibert C. Mitochondria: roles in pulmonary hypertension.Int J Biochem Cell Biol. 2014; 55: 93-97Crossref PubMed Scopus (38) Google Scholar In the current issue of the Journal, Noly and colleagues8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar report their investigation of the relationship between RV function and mitochondrial respiration measured in permeabilized cardiac fibers in a chronic model of thromboembolic pulmonary hypertension.8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar This report illustrates the timeline of mitochondrial respiratory dysfunction in the setting of RV failure, showing that (1) it occurs early and persists unchanged for as long as 12 weeks, (2) its severity correlates with the severity of RV dysfunction, and (3) it is associated with mitochondrial structural abnormalities without changes in the number of mitochondria. Although this study provides an important contribution to our understanding of mitochondrial dysfunction associated with RV failure secondary to pulmonary hypertension, its findings need to be interpreted within the broader context of myocardial bioenergetics. The flow of electrons in the mitochondrial respiratory chain is a tightly regulated process coupled with oxidative phosphorylation (production of adenosine triphosphate). Lower mitochondrial oxygen consumption can result from multiple causes, such as (1) decreased electron flow in the respiratory chain as a result of changes in the mitochondrial membrane potential, (2) functional or structural alterations in the respiratory chain proteins, and (3) decreased production of reduced nicotinamide adenine dinucleotide or reduced flavin adenine dinucleotide by the Krebs cycle.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar, 6Chan S.Y. Rubin L.J. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.Eur Respir Rev. 2017; 26 (Erratum in: Eur Respir Rev. 2018;27(147))Crossref PubMed Scopus (40) Google Scholar, 7Freund-Michel V. Khoyrattee N. Savineau J.P. Muller B. Guibert C. Mitochondria: roles in pulmonary hypertension.Int J Biochem Cell Biol. 2014; 55: 93-97Crossref PubMed Scopus (38) Google Scholar Noly and colleagues8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar used several substrates that fed electrons to different complexes of the mitochondrial respiratory chain, demonstrating decreased oxygen consumption with all of them. Although this approach suggests a compromise of the whole mitochondrial respiratory chain, it failed to identify a defect in a specific respiratory complex. Unfortunately, Noly and colleagues8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar did not use selective inhibitors of the respiratory complexes, which might have helped to identify specific sites within the chain. In addition, other causes of decreased mitochondrial respiration, such as changes in mitochondrial membrane potential or decrease in the production of reducing equivalents (reduced flavin adenine dinucleotide or reduced nicotinamide adenine dinucleotide) were not investigated. Mitochondrial hyperpolarization, a known phenomenon during RV failure that decreases respiration, was not investigated.4Ryan J.J. Archer S.L. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.Circulation. 2015; 131: 1691-1702Crossref PubMed Scopus (126) Google Scholar, 5Reddy S. Bernstein D. Molecular mechanisms of right ventricular failure.Circulation. 2015; 132: 1734-1742Crossref PubMed Scopus (102) Google Scholar, 6Chan S.Y. Rubin L.J. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.Eur Respir Rev. 2017; 26 (Erratum in: Eur Respir Rev. 2018;27(147))Crossref PubMed Scopus (40) Google Scholar, 7Freund-Michel V. Khoyrattee N. Savineau J.P. Muller B. Guibert C. Mitochondria: roles in pulmonary hypertension.Int J Biochem Cell Biol. 2014; 55: 93-97Crossref PubMed Scopus (38) Google Scholar Although changes in substrate oxidation were not specifically investigated, Noly and colleagues8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar claim that their results do not support the presence of a metabolic shift from glucose to fatty acid oxidation. This can be primarily concluded from observing similar maximum rates of oxidation for fatty acids (palmitoyl-coenzyme A) as for intermediaries of glucose oxidation (pyruvate, succinate) in the sham and experimental groups. These findings can also be interpreted differently. Because respiration with intermediaries of glucose oxidation as substrates is depressed while fatty acid oxidation is maintained at the same levels as in the sham group, an argument can be made that this is evidence of preservation of fatty acid oxidation relative to glucose oxidation in the experimental group. Not surprisingly, as the severity of RV dysfunction increases, mitochondrial maximum respiratory capacity decreases. Although Noly and colleagues8Noly P.E. Piquereau J. Coblence M. Ataam J.A. Guihaire J. Rucker-Martin C. et al.Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.J Thorac Cardiovasc Surg. 2020; 159: 129-140Abstract Full Text Full Text PDF Scopus (5) Google Scholar were not able to prove causation, they identified an important association between a metabolic derangement and right ventricular function that deserves further investigation. Finally, there were significant mitochondrial structural abnormalities observed at the end of the 12-week experiments. Although these changes likely represent irreversible mitochondrial damage, it is likely that they were preceded by less severe, only functional—and as such, potentially reversible—changes. Our ability to identify and target early derangements in mitochondrial function may provide opportunities for therapeutic interventions in right heart failure.9Culley M.K. Chan S.Y. Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains.J Clin Invest. 2018; 128: 3704-3715Crossref PubMed Scopus (74) Google Scholar Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertensionThe Journal of Thoracic and Cardiovascular SurgeryVol. 159Issue 1PreviewWe aimed to assess the mitochondrial respiratory capacities in the right ventricle in the setting of ventricular remodeling induced by pressure overload. Full-Text PDF Open Archive