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LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy

ABSTRACT: Mutations in the LMNA gene, encoding lamin A/C, are implicated in laminopathies and can lead to dilated cardiomyopathy and heart failure. However, the underlying mechanisms remain unclear. Here, we generated human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) from a patient carrying the LMNA p.His222Pro (c.665A>C) mutation and an isogenic CRISPR/Cas9-corrected control. Although differentiation efficiency and sarcomere organization were comparable, 3D cardiac organoids composed of LMNA mutant hiPSC-CMs displayed significantly reduced contractility compared to control organoids. Transcriptomic, biochemical and functional analyses revealed impaired mitochondrial calcium uniporter (MCU) complex activity in LMNA mutant hiPSC-CMs, marked by decreased MCU expression, an elevated MICU1:MCU ratio, and increased phosphorylation of pyruvate dehydrogenase (PDH) at Ser232 and PDH Ser300 – indicative of reduced mitochondrial calcium uptake. These defects were accompanied by decreased mitochondrial respiration and ATP production. Notably, treatment with the MCU activator amorolfine restored mitochondrial calcium uptake and contractility in LMNA mutant hiPSC-CMs. These findings identify mitochondrial calcium dysregulation as a key downstream consequence of the LMNA p.H222P mutation. Our results establish a mechanistic link between LMNA-associated cardiomyopathy and impaired mitochondrial function, highlighting the MCU complex as a potential therapeutic target in human cardiac laminopathy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304575 | GEO | 2026/07/27

REPOSITORIES: GEO

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