PT  - JOURNAL ARTICLE
AU  - Chelko, Stephen P.
AU  - Keceli, Gizem
AU  - Carpi, Andrea
AU  - Doti, Nunzianna
AU  - Agrimi, Jacopo
AU  - Asimaki, Angeliki
AU  - Beti, Carlos Bueno
AU  - Miyamoto, Matthew
AU  - Amat-Codina, Nuria
AU  - Bedja, Djahida
AU  - Wei, An-Chi
AU  - Murray, Brittney
AU  - Tichnell, Crystal
AU  - Kwon, Chulan
AU  - Calkins, Hugh
AU  - James, Cynthia A.
AU  - O’Rourke, Brian
AU  - Halushka, Marc K.
AU  - Melloni, Edon
AU  - Saffitz, Jeffrey E.
AU  - Judge, Daniel P.
AU  - Ruvo, Menotti
AU  - Kitsis, Richard N.
AU  - Andersen, Peter
AU  - Di Lisa, Fabio
AU  - Paolocci, Nazareno
TI  - Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
AID  - 10.1126/scitranslmed.abf0891
DP  - 2021 Feb 17
TA  - Science Translational Medicine
PG  - eabf0891
VI  - 13
IP  - 581
4099  - http://stm.sciencemag.org/content/13/581/eabf0891.short
4100  - http://stm.sciencemag.org/content/13/581/eabf0891.full
AB  - Arrhythmogenic cardiomyopathy (ACM) can lead to sudden cardiac death due to myocyte cell death and ventricular dysfunction. Chelko et al. investigated the mechanism underlying exercise-induced myocyte death in mice with desmoglein-2 mutations, which are linked to ACM. They found that intracellular calcium overload in the mutant mouse hearts was associated with calpain-1 activation, calpastatin depletion, and cell death. In the mouse model and tissue from patients with ACM, mitochondrial apoptosis-inducing factor (AIF) translocation to the nucleus was implicated in the process, and treatment with an AIF-mimetic could prevent cell death. This study highlights a signaling pathway that could potentially be targeted for ACM therapy.Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload–induced necrosis. When cardiomyocytes differentiated from Dsg2mut/mut embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.