| First Author | Beak JY | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 6 | Pages | 101358 |
| PubMed ID | 34756888 | Mgi Jnum | J:315160 |
| Mgi Id | MGI:6830704 | Doi | 10.1016/j.jbc.2021.101358 |
| Citation | Beak JY, et al. (2021) The nuclear receptor RORalpha preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy. J Biol Chem 297(6):101358 |
| abstractText | Preserving optimal mitochondrial function is critical in the heart, which is the most ATP-avid organ in the body. Recently, we showed that global deficiency of the nuclear receptor RORalpha in the "staggerer" mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. However, the mechanisms underlying these observations have not been defined previously. Here, we used pharmacological and genetic gain- and loss-of-function tools to demonstrate that RORalpha regulates cardiomyocyte mitophagy to preserve mitochondrial abundance and function. We found that cardiomyocyte mitochondria in staggerer mice with lack of functional RORalpha were less numerous and exhibited fewer mitophagy events than those in WT controls. The hearts of our novel cardiomyocyte-specific RORalpha KO mouse line demonstrated impaired contractile function, enhanced oxidative stress, increased apoptosis, and reduced autophagic flux relative to Cre(-) littermates. We found that cardiomyocyte mitochondria in "staggerer" mice with lack of functional RORalpha were upregulated by hypoxia, a classical inducer of mitophagy. The loss of RORalpha blunted mitophagy and broadly compromised mitochondrial function in normoxic and hypoxic conditions in vivo and in vitro. We also show that RORalpha is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that enhanced expression of RORalpha increases caveolin-3 abundance and enhances mitophagy. Finally, knockdown of RORalpha impairs cardiomyocyte mitophagy, compromises mitochondrial function, and induces apoptosis, but these defects could be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for RORalpha in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying RORalpha-mediated cardioprotection. |
