Dysregulation of N-terminal acetylation causes cardiac arrhythmia and cardiomyopathy

Daisuke Yoshinaga, Isabel Craven, Rui Feng, Maksymilian Prondzynski, Kevin Shani, Yashasvi Tharani, Joshua Mayourian, Milosh Joseph, David Walker, Raul H. Bortolin, Chrystalle Katte Carreon, Bridget Boss, Sheila Upton, Kevin Kit Parker, William T. Pu and Vassilios J. Bezzerides ()
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Daisuke Yoshinaga: Harvard Medical School
Isabel Craven: Harvard Medical School
Rui Feng: Harvard Medical School
Maksymilian Prondzynski: Harvard Medical School
Kevin Shani: Harvard John A. Paulson School of Engineering and Applied Sciences
Yashasvi Tharani: Harvard Medical School
Joshua Mayourian: Harvard Medical School
Milosh Joseph: Harvard Medical School
David Walker: Harvard Medical School
Raul H. Bortolin: Harvard Medical School
Chrystalle Katte Carreon: Harvard Medical School
Bridget Boss: Dartmouth Hitchcock Medical Center
Sheila Upton: Dartmouth Hitchcock Medical Center
Kevin Kit Parker: Harvard John A. Paulson School of Engineering and Applied Sciences
William T. Pu: Harvard Medical School
Vassilios J. Bezzerides: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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 NAA10R4S variant reduced enzymatic activity, decreased NAA10-NAA15 complex formation, and destabilized the enzymatic complex N-terminal acetyltransferase A. In NAA10R4S/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 NAA10R4S/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 NAA10R4S/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.

Date: 2025
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DOI: 10.1038/s41467-025-58539-2

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