Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy

Stephen P. Chelko, Gizem Keceli, Andrea Carpi, Nunzianna Doti, Jacopo Agrimi, Angeliki Asimaki, Carlos Bueno Beti, Matthew Miyamoto, Nuria Amat-Codina, Djahida Bedja, An Chi Wei, Brittney Murray, Crystal Tichnell, Chulan Kwon, Hugh Calkins, Cynthia A. James, Brian O'Rourke, Marc K. Halushka, Edon Melloni, Jeffrey E. SaffitzDaniel P. Judge, Menotti Ruvo, Richard N. Kitsis, Peter Andersen, Fabio Di Lisa, Nazareno Paolocci

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbereabf0891
JournalScience translational medicine
Volume13
Issue number581
DOIs
StatePublished - Feb 17 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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