Morphological Stages of Mitochondrial Vacuolar Degeneration in Phenylephrine-Stressed Cardiac Myocytes and in Animal Models and Human Heart Failure

Background and objectives: Derangements in mitochondrial integrity and function constitute an important pathophysiological feature in the pathogenesis of heart failure (HF) and play an important role in myocardial remodeling and systolic dysfunction. In systolic HF, we and others have shown an imbalance in mitochondrial dynamics toward mitochondrial fission and fragmentation with evidence of mitophagy, mitochondrial vacuolar degeneration, and impairment in mitochondrial oxidative capacity. The morphological stages of mitochondrial vacuolar degeneration have not been defined. We sought to elucidate the progressive stages of mitochondrial vacuolar degeneration, which would serve as a measure to define, morphologically, the severity of mitochondrial damage. Materials and Methods: Transmission electron microscopy was used to study mitochondrial morphology and pathology in phenylephrine-stressed cardiac myocytes in vitro and in left ventricular myocardium from a rat model of pressure overload induced systolic dysfunction and from patients with systolic HF. Results: In phenylephrine-stressed cardiomyocytes for two hours, alterations in mitochondrial cristae morphology (Stage A) and loss and dissolution of mitochondrial cristae in one (Stage B) or multiple (early Stage B -> C) mitochondrion area(s) were evident in the earliest stages of mitochondrial vacuolar degeneration. Mitochondrial swelling and progressive dissolution of mitochondrial cristae (advanced Stage B -> C), followed by complete loss and dissolution of mitochondrial cristae and permeabilization and destruction of inner mitochondrial membrane (Stage C) then outer mitochondrial membrane rupture (Stage D) constituted advanced stages of mitochondrial vacuolar degeneration. Similar morphological changes in mitochondrial vacuolar degeneration were seen in vivo in animal models and in patients with systolic HF; where about 60-70% of the mitochondria are mainly observed in stages B -> C and fewer in stages C and D. Conclusion: Mitochondrial vacuolar degeneration is a prominent mitochondrial morphological feature seen in HF. Defining the progressive stages of mitochondrial vacuolar degeneration would serve as a measure to assess morphologically the severity of mitochondrial damage.