Defects in lamin A-Prohibitin crosstalk lead to ROS elevation and OxPhos imbalance in laminocardiomyopathy

Lamins are critical for maintaining nuclear homeostasis, chromosome positioning, and cellular mechanotransduction, which involves the transfer of mechanical signals from the cellular microenvironment to the nucleus. Recent studies have also highlighted the involvement of lamin A in mitochondrial homeostasis and the regulation of reactive oxygen species production. Missense mutations in lamin A are linked to a spectrum of diseases known as laminopathies, which include conditions such as dilated cardiomyopathy (DCM), muscular dystrophy, and progeria. One such mutation, K97E, is associated with DCM, causing severe cardiac complications that can lead to myocardial infarction in extreme cases. Our study reveals a detailed pathogenic cascade in K97E-transfected cells involving disrupted interaction with Prohibitin-2, a key mitochondrial protein. Mitochondria exhibit increased fission, reduced fusion, and fragmentation, due to OPA1 downregulation and DRP1 recruitment driven by actin cytoskeletal remodelling. Impaired Rho-ERK– FAK signalling reduces F-actin assembly, elevating G-actin, which further promotes mitochondrial fission. This feedback loop leads to mitochondrial depolarisation, ATP deficiency, and global metabolic catastrophe, in particular cholesterol metabolism, accompanied by elevated ROS. In cardiomyocytes, such dysfunction may underlie contractile deficits and arrhythmias. Our findings establish PHB2 as a critical node linking nuclear integrity, cytoskeletal architecture, and mitochondrial homeostasis, offering new insights into DCM pathogenesis and therapeutic targets. Our findings elucidate the pivotal role of lamin A in cellular energetics and mechanotransduction, offering novel insights into DCM pathophysiology, which in turn opens avenues for developing targeted therapeutic strategies.