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
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Allston, MA, USA.
Nat Commun. 2025 Apr 16;16(1):3604. 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 variant reduced enzymatic activity, decreased NAA10-NAA15 complex formation, and destabilized the enzymatic complex N-terminal acetyltransferase A. In NAA10-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-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-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.
包括NAA10在内的N端乙酰转移酶催化N端乙酰化，这是一种进化上保守的共翻译和翻译后修饰。然而，关于N端乙酰化在心脏稳态中的作用知之甚少。为了深入了解心脏依赖的NAA10功能，我们研究了一个先前未鉴定的NAA10变体p.(Arg4Ser)，它在一个大家族中与QT延长、心肌病和发育迟缓相关。在这里，我们表明NAA10变体降低了酶活性，减少了NAA10-NAA15复合物的形成，并使酶复合物N端乙酰转移酶A不稳定。在NAA10诱导的多能干细胞衍生的心肌细胞（iPSC-CMs）中，晚期钠电流和缓慢延迟整流钾电流的失调导致严重的复极异常，这与临床QT延长一致。由NAA10-iPSC-CMs生成的工程心脏组织收缩力显著降低，肌节紊乱，这与该家族的心肌病表型一致。蛋白质组学研究揭示了代谢途径和心脏结构蛋白的失调。我们确定了使NAA10-iPSC-CMs表型正常化的小分子和基因疗法。我们的研究定义了N端乙酰化在心脏调节中的作用，并阐明了由NAA10功能障碍引起的QT延长、心律失常和心肌病的潜在机制。
