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Cardiac Organoids for Modeling Hypertrophic Cardiomyopathy

ABSTRACT: BACKGROUND: MYBPC3 is one of the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms of how mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. Thus, advancing in-vitro studies to define these mechanisms of mutations leading to HCM are still warranted. Thus, the primary objective of this study was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 mutation utilizing isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

ORGANISM(S): Homo sapiens

PROVIDER: GSE262876 | GEO | 2025/01/28

REPOSITORIES: GEO

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Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

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Cardiac Organoids for Modeling Hypertrophic Cardiomyopathy

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