Exercise-induced sudden cardiac death is caused by mitochondrio-nuclear translocation of AIF

Abstract

Irrespective of the underlying risk factors, myocyte cell death is a common feature in cardiac disorders. In particular, arrhythmogenic cardiomyopathies (ACMs) are characterized by an increased incidence of apoptotic and necrotic cardiac myocytes. Since cardiac myocytes are predominantly post-mitotic, they are typically replaced by fibrous tissue, which further interferes with the electrophysiology of the heart, adding to the disruption of the cardiac conduction system and, thus, ACM progression. Notably, ACM patients exhibit poor prognosis and increased risk of sudden cardiac death in association with exercise. Thus, ACM is one of the rare conditions in which exercise is detrimental rather than beneficial for organismal health. However, the underlying mechanisms of this intriguing, but well-established, observation remain poorly understood. In their recent study, Chelko et al. used homozygous desmoglein-2 mutant mice (Dsg2), which exhibit multiple features of human ACM, to elegantly unveil the molecular underpinnings of the exerciseinduced myocyte cell death in ACM. At the core of their proposed mechanistic cascade lies the apoptosis-inducing factor (AIF), a pro-apoptotic signaling molecule that is normally located in the mitochondrial intermembrane space. However, in response to apoptotic cues, AIF moves to the nucleus, thereby triggering DNA fragmentation and cell death. Chelko et al. found that almost half of Dsg2 mice die before finishing an eleven-week protocol of endurance swimming, as compared to less than 10% in the case of WT controls. Trained Dsg2 mice that did not die suffered from severe biventricular dilation and systolic dysfunction, and showed electrocardiograghic signs of impaired cardiac depolarization and repolarization. Concurrently, Dsg2 hearts exhibited exaggerated fibrosis, immune cell infiltration, and increased abundance of necrotic cardiomyocytes, as determined by highmobility-group box-1 immunostaining. The authors went on to show that Dsg2 hearts overexpress the Ca-activated cysteine protease calpain 1 (CAPN1), which was mainly localized at mitochondria. The cytosolto-mitochondria translocation of CAPN1 appeared to be a prerequisite for its Ca-dependent activation. The authors also attributed such increases in CAPN1 activity to the reduced abundance of its endogenous inhibitor, calpastatin (CAST) in Dsg2 hearts. In support of this notion, CAST overexpression or treatment with the CAPN1 inhibitor, calpeptin, delayed myocyte cell death induced by Ca overload or CAPN1 in vitro. In an effort to determine the mitochondrial effectors responsible for cardiac myocyte necrosis in Dsg2 mice, the authors examined key mediators of mitochondrial cell death. Specifically, they examined cytochrome C and apoptosis-inducing factor-1, mitochondrial (AIFM1, best known as AIF). While cytochrome C was not changed in Dsg2 hearts, AIF exhibited significant calpain-mediated truncation (which removes a hydrophobic domain from AIF that retains it at the mitochondrial inner membrane), mitochondrio-nuclear translocation and chromatin binding in response to exercise. Importantly, Chelko et al. showed that truncated AIF undergoes nuclear translocation not only in the myocardium of exercised Dsg2 mice, but also in ventricular samples of patients with ACM. In an interesting twist of their study, the authors demonstrated that a major proportion of cleaved AIF in Dsg2 mice is oxidized, an effect which they attributed to exaggerated exercise-triggered oxidative stress due to an insufficient mitochondrial thioredoxin-2 ROS buffering system. In turn, the degree of AIF oxidation was found to increase its