RT Journal Article
SR Electronic
T1 Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eabf0891
DO 10.1126/scitranslmed.abf0891
VO 13
IS 581
A1 Chelko, Stephen P.
A1 Keceli, Gizem
A1 Carpi, Andrea
A1 Doti, Nunzianna
A1 Agrimi, Jacopo
A1 Asimaki, Angeliki
A1 Beti, Carlos Bueno
A1 Miyamoto, Matthew
A1 Amat-Codina, Nuria
A1 Bedja, Djahida
A1 Wei, An-Chi
A1 Murray, Brittney
A1 Tichnell, Crystal
A1 Kwon, Chulan
A1 Calkins, Hugh
A1 James, Cynthia A.
A1 O’Rourke, Brian
A1 Halushka, Marc K.
A1 Melloni, Edon
A1 Saffitz, Jeffrey E.
A1 Judge, Daniel P.
A1 Ruvo, Menotti
A1 Kitsis, Richard N.
A1 Andersen, Peter
A1 Di Lisa, Fabio
A1 Paolocci, Nazareno
YR 2021
UL http://stm.sciencemag.org/content/13/581/eabf0891.abstract
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.