The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Molecular Cardiology

Background:

• Optimal mitochondrial function is essential for the heart's high energy demands.
• Previous studies indicated RORα deficiency exacerbates cardiac hypertrophy and mitochondrial dysfunction.

Purpose of the Study:

• To elucidate the mechanisms by which RORα influences cardiomyocyte mitochondrial function.
• To investigate the role of RORα in regulating mitophagy.

Main Methods:

• Utilized pharmacological and genetic gain- and loss-of-function tools in mouse models.
• Generated a novel cardiomyocyte-specific RORα knockout (KO) mouse line.
• Performed in vivo and in vitro experiments under normoxic and hypoxic conditions.

Main Results:

• RORα deficiency in "staggerer" mice led to fewer cardiomyocyte mitochondria and reduced mitophagy.
• Cardiomyocyte-specific RORα KO mice exhibited impaired contractile function, increased oxidative stress, and apoptosis.
• RORα was identified as a direct transcriptional regulator of caveolin-3, a mitophagy mediator.
• Loss of RORα blunted mitophagy and compromised mitochondrial function, effects rescued by caveolin-3 overexpression.

Conclusions:

• RORα plays a novel and critical role in regulating cardiomyocyte mitophagy via caveolin-3.
• RORα-mediated mitophagy is essential for preserving mitochondrial abundance and function, thereby protecting against cardiac dysfunction.
• These findings expand the understanding of RORα's cardioprotective mechanisms.