# Attenuated lamin A–prohibitin2 interaction leads to mitochondrial dysfunction in LMNA 289 A>G–mediated dilated cardiomyopathy

## TL;DR

A mutation in lamin A disrupts its interaction with prohibitin2, leading to mitochondrial dysfunction and contributing to dilated cardiomyopathy.

## Contribution

This study is the first to elucidate lamin A's role in cellular bioenergetics and mechanotransduction in dilated cardiomyopathy.

## Key findings

- Reduced lamin A K97E and prohibitin2 interaction causes mitochondrial fragmentation and ATP deficiency.
- Impaired RhoA/ERK/FAK signaling disrupts actin assembly and promotes mitochondrial fission.
- Mitochondrial dysfunction leads to depolarization, reduced glycolytic capacity, and elevated superoxide levels.

## Abstract

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.