Key result
LMNA K97E mutation disrupts lamin A-prohibitin 2 interaction to drive mitochondrial dysfunction in DCM.
Why the study?
LMNA missense mutations like K97E cause DCM with severe phenotypes, but the mechanisms linking lamin A to mitochondrial homeostasis and disease pathology remained to be elucidated.
The lamin A K97E mutation associated with dilated cardiomyopathy disrupts lamin A-PHB2 interaction, driving mitochondrial fragmentation, energetic deficiency, and defective mechanotransduction.
Identifies lamin A-PHB2 disruption as a DCM mechanism; extends mitochondrial-lamin links but leaves open therapeutic translation.
Lamins are critical in maintaining nuclear homeostasis, chromosome positioning, and modulating mechanotransduction. Recent studies indicated the involvement of lamin A in mitochondrial homeostasis and the regulation of superoxide. Missense mutations in LMNA are linked to a spectrum of diseases known as laminopathies, which include conditions, such as dilated cardiomyopathy (DCM), muscular dystrophy, and progeria. K97E is one such mutation, which leads to DCM with severe phenotypes. In this study, we established direct reduction of interaction between lamin A K97E and prohibitin 2. As a sequel, mitochondria exhibited reduced fusion, elevated fragmentation, and ATP deficiency. On the other hand, impaired RhoA/extracellular signal-regulated kinase/focal adhesion kinase signaling cascade disrupted filamentous actin assembly, thereby promoting actin-mitochondria association, further facilitating mitochondrial fission. This feedback loop led to mitochondrial depolarization, and global metabolic derangement, in particular, reduced glycolytic capacity and incomplete fatty acid oxidation accompanied by elevated superoxide levels. In cardiomyocytes, such dysfunction may be correlated with contractile defects and arrhythmias. Thus, our findings elucidated for the first time the pivotal role of lamin A in cellular bioenergetics and mechanotransduction, offering novel insights into DCM pathophysiology, which could open newer vistas for developing targeted therapeutic strategies.
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Nath et al. (2026) studied Dilated cardiomyopathy. LMNA K97E (289 A>G) mutation vs. Wild-type (WT) lamin A was evaluated on Lamin A-prohibitin 2 (PHB2) interaction and cellular bioenergetics. The LMNA K97E mutation attenuates lamin A-prohibitin 2 interaction, leading to mitochondrial fragmentation, ATP deficiency, and actin destabilization in cellular models of dilated cardiomyopathy.
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