Targeting mitochondrial dysfunction in the treatment of heart failure

Figures & data

Figure 1. Depiction of mitochondrial inner membrane and electron transport chain consisting of complexes I through V. ROS are generated at complexes I and III. Excessive ROS production can lead to mitochondrial and cardiomyocyte dysfunction by inhibiting the TCA cycle enzymes and ATP synthase, and by damaging mtDNA. Adapted with permission from Okonko DO, et al., Nat Rev Cardiol 2015 [14]. CK: creatine kinase; CoQ₁₀: coenzyme Q₁₀; Cyt C: cytochrome c; mtDNA: mitochondrial DNA; Pi: inorganic phosphate; ROS: reactive oxygen species; TCA: tricarboxylic acid.

Figure 2. Transmission electron micrographs of LV mitochondria in normal dogs and dogs with HF. Top left: normal 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. Adapted with permission from Sabbah HN, et al. J Mol Cell Cardiol 1992 [13]. HF: heart failure; ID: intercalated disc; LV: left ventricular; M: mitochondrium.

Figure 3. Mean (± SEM) protein levels of PGC-1α (top) and phosphorylated PGC-1α (bottom) in LV myocardium of normal dogs and those with HF. Adapted from Gupta RC, et al. J Am Coll Cardiol 2013 [27]. HF: heart failure; LV: left ventricular; PGC-1α; peroxisome proliferator-activated receptor coactivator-1α; SEM: standard error of the mean.

Figure 4. Dysregulation of mitochondria fission and fusion proteins in LV myocardium of dogs with chronic HF. Bar graphs (mean ± SEM) show significant reduction in Mfn-2 and dominant OPA-1 mitochondrial fusion protein levels (top) and significant increases in Fis1 and Drp1 mitochondrial fission protein levels (bottom) in LV myocardium of dogs with chronic HF compared to normal dogs. Adapted from Sabbah HN, et al. Circulation 2014 [33]. Drp1: dynamin-related protein-1; Fis1: fission-1; HF: heart failure; LV: left ventricular; Mfn-2: mitofusion-2, NL: normal; OPA-1: optic atrophy-1; SEM: standard error of the mean.

Figure 5. Reduction in mitochondrial membrane potential in LV myocardium of dogs with chronic HF. Bar graphs (mean ± SEM) show significant reduction in mitochondrial membrane potential (top left), significant increase in cytochrome c in cardiomyocyte cytosolic fraction (top right), significant reduction in the maximum rate of ATP synthesis by mitochondria in cardiomyocytes (bottom left), and significant reduction in 18:2 cardiolipin (bottom right) in LV myocardium of dogs with chronic HF compared with normal dogs. Adapted with permission from Sharov VG, et al. J Mol Cell Cardiol 2007 [36] and Sharov VG, et al. Heart Fail Rev 2005 [35]. HF: heart failure; LV: left ventricular, NL; normal, SEM: standard error of the mean.

Figure 6. LV myocardium protein levels of various metabolic proteins in dogs with chronic HF treated with (CAP) or without (CON) capadenoson compared to normal dogs (NL). Bar graphs (mean ± SEM) show changes in UCP-2 (top left), UCP-3 (top middle), CS (top right), GLUT-1 (bottom left), GLUT-4 (bottom middle), and mCPT-1 (bottom right). Adapted with permission from Sabbah HN, et al. Circ Heart Fail 2013 [46]. CAP: HF treated with capadenoson; CS: mitochondrial citrate synthase; CON: untreated HF; GLUT: glucose transporter; LV: left ventricular, mCPT-1; muscle carnitine palmitoyl transferase-1; NL: normal; SEM: standard error of the mean; UCP: mitochondrial uncoupling protein. *p < 0.05 vs NL; **p < 0.05 vs. CON.

Figure 7. Effect of elamipretide treatment in dogs with HF. Change (Δ, treatment effect) between pretreatment and 12 weeks post-treatment for left ventricular EDV, ESV, EF, and FAS (left) and plasma nt-pro BNP (right) in untreated HF control dogs (HF-CON) and HF dogs treated with elamipretide (HF+ELA). All bar graphs are depicted as mean ± SEM. Adapted with permission from Sabbah HN, et al. Circ Heart Fail 2016 [37]. EDF: end-diastolic volume; EF: ejection fraction; ESV: end-systolic volume; FAS: fractional area of shortening; HF: heart failure; nt-pro BNP: n-terminal pro-brain natriuretic peptide; SEM: standard error of the mean.

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