Targeting the Mitochondria in Heart Failure: A Translational Perspective

Abstract

The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as "energy-deprived" and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities. Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species and a marked reduction in on demand adenosine triphosphate synthesis. Correcting mitochondrial dysfunction therefore offers considerable potential as a new therapeutic approach to improve overall cardiac function, quality of life, and survival for patients with HF.

Keywords: ADP, adenosine diphosphate; ATP, adenosine triphosphate; CI (to V), complex I (to V); Drp, dynamin-related protein; ETC, electron transport chain; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; MPTP, mitochondrial permeability transition pore; Mfn, mitofusin; OPA, optic atrophy; PGC, peroxisome proliferator-activated receptor coactivator; PINK, phosphatase and tensin homolog–inducible kinase; ROS, reactive oxygen species; TAZ, tafazzin; cardiolipin; heart failure; mitochondria; mtDNA, mitochondrial deoxyribonucleic acid; myocardial energetics; oxidative phosphorylation.

Graphical abstract

Figure 1

Mitochondrial Inner Membrane and Electron Transport Chain Depiction of mitochondrial inner membrane and electron transport chain consisting of complexes I through V (CI to CV). Reactive oxygen species (ROS) are generated at CI and CIII. Excessive ROS production can lead to mitochondrial and cardiomyocyte dysfunction by inhibiting the tricarboxylic acid (TCA) cycle enzymes and adenosine triphosphate (ATP) synthase, and by damaging mitochondrial deoxyribonucleic acid (mtDNA). CK = creatine kinase; CoQ₁₀ = coenzyme Q₁₀; Cyt C = cytochrome c; e⁻ = electrons; Pi = inorganic phosphate.

Figure 2

Imbalance Between Energy Supply and Demand in the Development of HF Schematic of the imbalance between energy supply and demand in the development of heart failure (HF). ATP = adenosine triphosphate.

Figure 3

LV Mitochondria in Normal Dogs and Dogs With HF Transmission electron micrographs of left ventricular (LV) mitochondria in normal dogs and dogs with heart failure (HF). (Top left) Normal dog showing predominantly normal, large mitochondria with tightly packed cristae and electron-dense matrix, with insert depicting various structural components of mitochondria. (Top right) Coronary microembolization-induced HF showing mild abnormalities of mitochondria in the form of clearance of electron-dense matrix. (Bottom left) Coronary microembolization-induced HF showing moderate abnormalities of mitochondria in the form of reduced organelle size and marked disorganization of cristae. (Bottom right) Coronary microembolization-induced HF showing severe mitochondrial injury with inner and outer membrane disruption and myelinization. ID = intercalated disk; M = mitochondrion.

Figure 4

Fusion- and Fission-Mediating Proteins in Normal and HF Dogs (Left) Fusion-mediating proteins include dominant optic atrophy (OPA)-1 and mitofusin (Mfn)-2 and fission-mediating proteins include fission (Fis)-1 and dynamin-related protein (Drp)-1. (Right) Levels of fusion-mediating proteins and fission-mediating proteins in left ventricular myocardium of normal dogs (NL) and dogs with coronary microembolization–induced heart failure (HF). Data are shown as mean ± SEM. du = densitometric units.

Figure 5

Mitophagy Signaling in Normal Healthy and Damaged Mitochondria Schematic diagrams depicting mitophagy signaling in normal healthy mitochondria (top) and in damaged mitochondria (bottom). Activation of phosphatase and tensin homolog–inducible kinase (PINK)-1 by adenosine monophosphate–activated protein kinase (AMPK) α-2 regulation of PINK-1. (Top) Import of PINK-1 into healthy mitochondria via translocase of the outer membrane–translocase of the inner membrane (TOM/TIM) import complex. PINK-1 undergoes proteolytic cleavage by presenilins-associated rhomboid-like (PARL) and cleaved PINK-1 retro-translocates to the cytosol where it is degraded by proteasome. (Bottom) When mitochondria are damaged, import of PINK-1 is abrogated and it accumulates on the outer membrane, which leads to its phosphorylation by AMPKα2. Phosphorylated PINK-1 recruits the E3 ubiquitin ligase Parkin to the mitochondria from the cytosol. PINK-1 phosphorylates both Parkin and mitofusion (Mfn)-2 promoting ubiquitination (Ub) of mitochondrial substrates. The valosin-containing protein (VCP) transports ubiquinated mitochondria to the mitophagosome for their degradation.

Figure 6

Down-Regulation of PINK-1, AMPKα2, Parkin, Cytosolic Parkin, pMfn-2, and VCP Bar graphs depicting down-regulation of PINK-1, AMPKα2, Parkin (E3 ubiquitin ligase), cytosolic Parkin, phosphorylated (p) Mfn-2, and mitochondrial VCP in left ventricular myocardium of NL dogs and HF dogs. All proteins were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Data are shown as mean ± SEM. Abbreviations as in Figures 3, 4, and 5.

Figure 7

Measures of Mitochondrial Function (Left) Bar graphs depicting total cardiolipin level (CL) normalized to mitochondrial (MITO) protein (top), total (18:2)₄ CL normalized to MITO protein level (middle), and MITO complex IV activity (bottom) in left ventricular myocardium of NL dogs, untreated HF control dogs (HF-CON), and dogs with HF treated with elamipretide (HF+ELA). (Right) MITO states 3 and 4 respiration (top), MITO membrane potential (middle), and maximum rate of ATP synthesis (bottom) in left ventricular myocardium of NL dogs, untreated HF-CON dogs, and HF+ELA dogs. All bar graphs are depicted as mean ± SEM.

Figure 8

Changes in LV Myocardium Protein Levels of Various Proteins in NL, HF-CON, and HF-CAP Dogs Bar graphs depicting changes in LV myocardium protein levels of various metabolic and sarcoplasmic reticulum proteins in NL dogs, untreated HF-CON dogs CON, and dogs with HF treated with capadenoson (CAP). Data are shown as mean ± SEM. *p < 0.05 versus NL; **p < 0.05 versus CON. CS = citrate synthase; SERCA-2a = sarcoplasmic reticulum calcium adenosine triphosphatase; UCP = uncoupling protein; other abbreviations as in Figures 3, 4, and 7.