Mitochondrial Integrity Is Critical in Right Heart Failure Development

Abstract

Molecular processes underlying right ventricular (RV) dysfunction (RVD) and right heart failure (RHF) need to be understood to develop tailored therapies for the abatement of mortality of a growing patient population. Today, the armament to combat RHF is poor, despite the advancing identification of pathomechanistic processes. Mitochondrial dysfunction implying diminished energy yield, the enhanced release of reactive oxygen species, and inefficient substrate metabolism emerges as a potentially significant cardiomyocyte subcellular protagonist in RHF development. Dependent on the course of the disease, mitochondrial biogenesis, substrate utilization, redox balance, and oxidative phosphorylation are affected. The objective of this review is to comprehensively analyze the current knowledge on mitochondrial dysregulation in preclinical and clinical RVD and RHF and to decipher the relationship between mitochondrial processes and the functional aspects of the right ventricle (RV).

Keywords: mitochondria; oxidative stress; pulmonary hypertension; right heart failure.

Figure 1

Modifications of cardiac mitochondrial integrity in right heart failure. Principal processes of energy metabolism, the mitochondrial electron transport chain, oxidative phosphorylation, redox regulations, mitochondrial biogenesis and dynamics, and their impact on the sarcomere are depicted. Red arrows indicate alterations in right heart failure. The purple color indicates the pathological consequences of mitochondrial disintegration. For better clarity, the reaction equations are simplified. Abbreviations: ADS, antioxidative defense system; Cr, creatine; CK, creatine kinase; DRP1, dynamin-related protein1; HK, hexokinase; LC-FA, long-chain fatty acids; mPTP, mitochondrial permeability transition pore; NNT, nicotinamide nucleotide transhydrogenase; OPA1, optic atrophy 1; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; SOD, superoxide dismutase; TCA, tricarboxylic acid.