# Smarca4 maintains mitochondrial homeostasis and energy metabolism during cardiac development

## TL;DR

This study shows that Smarca4, a chromatin remodeling protein, is essential for maintaining mitochondrial function and energy production in developing heart and muscle cells.

## Contribution

The study identifies Smarca4 as a novel regulator of mitochondrial homeostasis through chromatin remodeling during vertebrate muscle development.

## Key findings

- Smarca4 deficiency in zebrafish leads to impaired cardiac and skeletal muscle function.
- Smarca4 loss reduces mitochondrial content and ATP production in heart and muscle cells.
- Smarca4 regulates genes involved in mitochondrial biogenesis and oxidative phosphorylation.

## Abstract

Mitochondrial metabolism is fundamental to cardiac and skeletal muscle function due to the high adenosine triphosphate (ATP) demand required for sustained contractility. Although mitochondrial dysfunction is central to metabolic myopathies, the epigenetic mechanisms regulating mitochondrial structure and function remain poorly defined. Here, we identify the SWI/SNF chromatin remodeling ATPase subunit Smarca4 as a critical regulator of mitochondrial homeostasis and cellular energy metabolism. Using a smarca4a-deficient zebrafish model (smarca4aa8−/−), we show that Smarca4 loss causes ventricular hypoplasia, pericardial edema, and disorganized skeletal muscle, leading to pronounced impairment of cardiac and muscular function. Heart-specific RNA-seq, ATAC-seq, and single-cell RNA-seq analyses revealed that Smarca4 deficiency reduces chromatin accessibility and suppresses the transcription of genes controlling mitochondrial biogenesis and oxidative phosphorylation. Consistently, high-resolution confocal imaging and Seahorse-based metabolic profiling demonstrated marked reductions in mitochondrial content, respiratory capacity, and ATP generation. AAV-mediated SMARCA4 knockdown in human cardiomyocytes and murine myotubes reproduced these mitochondrial defects. Collectively, these findings establish Smarca4 as a conserved chromatin remodeling factor linking nuclear regulation to mitochondrial energy homeostasis during vertebrate muscle development.

The online version contains supplementary material available at 10.1007/s00018-026-06168-3.