NAA10 and NAA15 mutations in cardiovascular disorders: Recent advances and mechanistic insights

N-terminal acetylation (NTA) is a ubiquitous eukaryotic post-translational modification catalyzed by Nα-acetyltransferases (NATs). Among the eight NAT families, the NatA complex-composed of the catalytic subunit NAA10 and auxiliary subunit NAA15-mediates N-terminal acetylation of ~40% of mammalian proteins. Pathogenic mutations in NAA10 or NAA15 disrupt NatA complex integrity or enzymatic activity, resulting in NAA10- or NAA15-related syndromes. Both disorders share overlapping clinical features, including developmental delay, intellectual disability, growth impairment, skeletal anomalies, and cardiac dysfunction. However, emerging clinical evidence highlights cardiac defects, particularly life-threatening arrhythmias and structural abnormalities, as the predominant phenotype contributing to the major cause of mortality in these syndromes. This review systematically dissects how distinct classes of NAA10 and NAA15 mutations perturb cardiac function through: (i) NatA complex assembly defects, (ii) catalytic dysfunction spanning impaired acetyltransferase activity and disrupted ribosome binding (iii) protein destabilization, and (iv) ion channel dysregulation, integrating clinical phenotypes with mechanistic insights from patient-derived iPSC-cardiomyocyte models and biochemical studies. We critically evaluate current methodologies and identify research gaps. Finally, we consider how mechanistic insights from these severe early-onset disorders-particularly regarding proteostasis failure and ion channel dysfunction-may extend beyond rare disease contexts to inform broader cardiac biology, including emerging concepts of proteostasis decline in cardiac ageing.