Dysregulation of N-terminal acetylation causes cardiac arrhythmia and cardiomyopathy

• Published in: Nature communications Vol. 16; no. 1; pp. 3604 - 23
• Main Authors: Yoshinaga, Daisuke, Craven, Isabel, Feng, Rui, Prondzynski, Maksymilian, Shani, Kevin, Tharani, Yashasvi, Mayourian, Joshua, Joseph, Milosh, Walker, David, Bortolin, Raul H., Carreon, Chrystalle Katte, Boss, Bridget, Upton, Sheila, Parker, Kevin Kit, Pu, William T., Bezzerides, Vassilios J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.04.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/100; 13/106; 13/107; 13/31; 13/51; 13/62; 13/89; 14; 14/10; 14/19; 14/63; 692/4019/592/2727; 692/4019/592/75/29/1938; 692/4019/592/75/74/1540; 82/58; 82/80; 82/81; 82/83; 9/30; 9/74; Abnormalities; Acetylation; Acetyltransferase; Animals; Arrhythmia; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Cardiac arrhythmia; Cardiomyocytes; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathy; Cell culture; Complex formation; Enzymatic activity; Female; Gene therapy; Heart; Homeostasis; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Ion channels; Male; Metabolic pathways; multidisciplinary; Muscle contraction; Myocytes, Cardiac - metabolism; N-terminal acetyltransferase; N-Terminal Acetyltransferase A - genetics; N-Terminal Acetyltransferase A - metabolism; N-Terminal Acetyltransferase E - genetics; N-Terminal Acetyltransferase E - metabolism; Pedigree; Phenotypes; Pluripotency; Post-translation; Potassium currents; Prolongation; Protein Processing, Post-Translational; Proteomics; Science; Science (multidisciplinary); Stem cells; Structural proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-58539-2

N-terminal acetyltransferases including NAA10 catalyze N-terminal acetylation, an evolutionarily conserved co- and post-translational modification. However, little is known about the role of N-terminal acetylation in cardiac homeostasis. To gain insight into cardiac-dependent NAA10 function, we studied a previously unidentified NAA10 variant p.(Arg4Ser) segregating with QT-prolongation, cardiomyopathy, and developmental delay in a large kindred. Here, we show that the NAA10 R4S variant reduced enzymatic activity, decreased NAA10-NAA15 complex formation, and destabilized the enzymatic complex N-terminal acetyltransferase A. In NAA10 R4S/Y -induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs), dysregulation of the late sodium and slow delayed rectifier potassium currents caused severe repolarization abnormalities, consistent with clinical QT prolongation. Engineered heart tissues generated from NAA10 R4S/Y -iPSC-CMs had significantly decreased contractile force and sarcomeric disorganization, consistent with the pedigree’s cardiomyopathic phenotype. Proteomic studies revealed dysregulation of metabolic pathways and cardiac structural proteins. We identified small molecule and genetic therapies that normalized the phenotype of NAA10 R4S/Y -iPSC-CMs. Our study defines the roles of N-terminal acetylation in cardiac regulation and delineates mechanisms underlying QT prolongation, arrhythmia, and cardiomyopathy caused by NAA10 dysfunction. N-terminal acetylation dysregulation in the heart causes severe arrhythmia and cardiomyopathy. The authors show that stem cell models demonstrate ion channel trafficking defects and sarcomeric disarray as the underlying mechanisms, with gene therapy reversing both phenotypes