Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure

Figure 1. Mitochondrial ultrastructural changes in heart failure. (A) Transmission electron micrograph of longitudinal section of left ventricular (LV) myocardium suggests that each intermyofibrillar mitochondrion extends from one Z band to another, and neighbors with adjacent sarcomeres. The T-tubules (T), which are invaginations of the plasma membrane, are surrounded by the junctional sarcoplasmic reticulum (JSR), and are interspersed between adjacent intermyofibrillar mitochondria. The longitudinal sarco/endoplasmic reticulum runs in a network configuration between adjacent intermyofibrillar mitochondria and sarcomeres. This topology of the intermyofibrillar mitochondria places them at the hub of calcium signaling by being physically tethered and functionally coupled with the adjacent organelles, particularly the endoplasmic reticulum. Photomicrograph is 40k X magnified, scale bar 0.5 μm. (B) Transmission electron micrograph of LV myocardium in systolic HF (HFrEF). Please refer to text in the body of manuscript for details. Yellow circles showing areas where lysosomes are fusing with surrounding mitochondria. Blue asterisks showing mitochondria at different stages of vacuolar…

Figure 2. Stages of mitochondrial vacuolar degeneration. (Stage A) Concentric remodeling of mitochondrial cristae (red dots) in an onion like pattern with widening of spaces between them (blue dashes). Stage A is encountered in stressed adult cardiac myocytes in vitro and is not appreciated in animal models of HF in vivo. (Stage B) Loss of mitochondrial cristae in a single mitochondrion area. (Stage B ➔ C) Loss of mitochondrial cristae in multiple mitochondrion areas. The inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) remain intact and there is no evidence of mitochondrial swelling. Advanced (Stage B ➔ C) mitochondrial swelling with advanced loss of mitochondrial cristae in multiple mitochondrion areas and permeabilization of IMM. (Stage C) Mitochondrial swelling and complete dissolution of mitochondrial cristae and IMM. (Stage D) include morphological changes in Stage C, along with rupture of the OMM (blue arrows). Image obtained and modified in permission from Chaanine et al. [11].

Figure 3. Percentage of mitochondria at different stages of mitochondrial vacuolar degeneration in stressed adult cardiomyocytes, and in HF with reduced ejection fraction (HFrEF). All data points are shown as box and whisker plots (lines showing median, 25th and 75th percentiles with whiskers showing minimum and maximum values in: (A) phenylephrine stressed adult cardiomyocytes, * p < 0.05 vs. ACM-Control, and † p < 0.05 vs. ACM-PE, 2h; (B) rat model of pressure overload induced HFrEF, * p < 0.05 vs. Rat-Normal; and (C) human HFrEF, * p < 0.05 vs. Human-Normal. Adapted with permission from Chaanine et al. [11]. ACM: adult cardiac myocyte. PE: phenylephrine.

Figure 4. Central illustration of perturbations in mitochondrial physiology and metabolism in compensated hypertrophy and in progression to overt systolic heart failure. Mitochondrial fission and changes in substrate utilization and metabolism in favor of glucose are evident early on in pathological compensated hypertrophy (CR: concentric remodeling). Transitioning to a decompensated state, moderate remodeling and early systolic dysfunction (MOD HF phenotype), is associated with mitochondrial fragmentation, enhanced degradation and decreased oxidative capacity. Derangements in fatty acid (FA) beta-oxidation and pyruvate metabolism are evident at this stage of HF, along with increases in mitochondrial matrix calcium (Ca2+) and reactive oxygen species (ROS). Progression to advanced, overt, systolic HF (HFrEF) is associated with severe impairment in mitochondrial function and decrease in mitochondrial biogenesis and mass, FA and glucose metabolism. OXPHOS: oxidative phosphorylation, MPT: mitochondrial permeability transition, BCAA: branched chain amino acids.

Figure 5. Illustration of key mitochondrial pathological findings in compensated hypertrophy and in progression to overt systolic heart failure. MDP: mitochondrial dynamic proteins, PTM: post-translational modification, ETC: electron transport chain Φ: No, Δ: Change.