Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

“…Emerging evidence suggests that the main site of superoxide generation in the mitochondria is the flavin mononucleotide group of complex I through reverse electron transfer, consistent with data that shows inhibition of succinate-related ROS generation by diphenyleneiodonium without affecting the flavin group of complex II [48][49][50]. Moreover, complex III of the mitochondrial respiratory chain generates ROS species through the ubiquinone-reactive sites, Q0 and Qi [51,52]. The redox activity of 66-kDa Src homology 2 domain-containing protein (p66Shc) within mitochondria has been shown to directly generate hydrogen peroxide through oxidation of cytochrome c without intermediate formation of superoxide anion [53,54].…”

Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk

“…At the cellular and animal levels, we showed that, in diabetes, the arrhythmic effect of mitoROS was via oxidative modification of RyR2, leading to increased spontaneous SR Ca 2+ leak, as S107 alone, a drug that inhibits RyR2 channel–mediated resting Ca 2+ leak, reversed the diabetic arrhythmic phenotypes, implying that IL-1β and mitoROS acted predominantly on the RyR2 to mediate their effects. Excessive SR Ca 2+ leak through oxidized RyR2 is known to increase free Ca 2+ ion transportation into mitochondria causing mitochondrial Ca 2+ overload, which subsequently results in more mitoROS production ( 45 ). This vicious cycle helps to sustain arrhythmia in DM.…”

Cobalt oxide nanoparticles induce oxidative stress and alter electromechanical function in rat ventricular myocytes

“…ATP must be generated in large amount to support the viability and contractile function of the myocardium. ATP, mostly derived from β-oxidation of free fatty acids and oxidative phosphorylation in the mitochondria [ 55 ], is consumed in the sarcomere contractile process (60–70%), as well as for the function of various ion pumps such as SERCA (30–40%) [ 55 ]. A decreased ATP availability determines a lower SERCA activity with a consequent prolongation of the time required for cytosolic Ca 2+ removal, as we observed (τ values).…”