Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy(405 views) Chelko SP, Keceli G, Carpi A, Doti N, Agrimi J, Asimaki A, Beti CB, Miyamoto M, Amat-codina N, Bedja D, Wei AC, Murray B, Tichnell C, Kwon C, Calkins H, James CA, O , #rourke B, Halushka MK, Melloni E, Saffitz JE, Judge DP, Ruvo M, Kitsis RN, Andersen P, Di Lisa F, Paolocci N
Sci Transl Med (ISSN: 1946-6234linking), 2021 Feb 17; 13(581): N/D-N/D.
Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA. stephen.chelko@med.fsu.edu npaoloc1@jhmi.edu., Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Department of Biomedical Sciences, University of Padova, Padova 35122, Italy., Institute of Biostructures and Bioimaging, CNR, Naples 80134, Italy., Molecular and Clinical Sciences Research Institute, St. George's, University of London, London WC1E 6BS, UK., Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia., Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Department of Medicine, University of Genova, Genova 16126, Italy., Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 20115, USA., Medical University of South Carolina, Charleston, SC 29425, USA., Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. stephen.chelko@med.fsu.edu npaoloc1@jhmi.edu.,
References: Not available.
Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
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 (Dsg2 (mut/mut)), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca(2+)) overload in Dsg2 (mut/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 Dsg2 (mut/mut) mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca(2+) overload-induced necrosis. When cardiomyocytes differentiated from Dsg2 (mut/mut) embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2 (mut/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.
Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(458 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote
Ntziachristos V, Cuénod CA, Fournier L, Balvay D, Pradel C, Siauve N, Clement O, Jouannot E, Lucidarme O, Vecchio SD, Salvatore M, Law B, Tung C-H, Jain RK, Fukumura D, Munn LL, Brown EB, Schellenberger E, Montet X, Weissleder R, Clerck ND, Postnov A * Tumor Imaging(476 views) Textbook Of In Vivo Imaging In Vertebrates (ISSN: 9780-4700), 2007 Jul 16; 1: 277-309. Impact Factor:1.148 ViewExport to BibTeXExport to EndNote