Biology subjects

Beak, J. Y.

Publications and source records attributed to Beak, J. Y..

3 recordsLinked to original sources

bioRxiv2026

The nuclear receptor ROR-alpha is a critical myogenic regulator of the cardiomyocyte transcriptome, including the alpha-1A adrenergic receptor

AimsWe recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (ROR) protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The underlying molecular basis for these salutary effects remains unclear. MethodsWe used RNA microarrays to profile the cardiac transcriptomes of "staggerer" (RORsg/sg) mice that carry a naturally occurring mutation in the ligand-binding domain of ROR, resulting in a global loss-of-function genetic model. We then used genetic and pharmacologic loss-and-gain of function studies in cultured cardiomyocytes to ascertain whether ROR regulates transcription of Adra1a, the gene that encodes the alpha-1A-adrenergic receptor (1A-AR). ResultsThe absence of functional ROR results in broad transcriptional changes in the heart providing a likely molecular basis for the RORsg/sg cardiac phenotype. In vivo and in vitro studies confirmed that ROR directly regulates Adra1a transcription. This effect is enhanced by hypoxia. ConclusionsCollectively these findings position ROR as a previously unrecognized central regulator of the cardiac myogenic transcriptome and the first recognized transcriptional regulator of Adra1a in cardiomyocytes. Future studies will probe the contribution of ROR-mediated transcriptional regulation of Adra1a to both the response to cardiomyocyte injury and maintenance of circadian biology.

physiology↗

bioRxiv2025

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart

Trametinib (Trm) is a highly selective MEK inhibitor that potently and persistently abrogates ERK1/2 activation. Trm initially was used to treat BRAF V600E-mutated melanoma but its FDA-approved indications are expanding rapidly. Trm generally is well tolerated but it can cause dose-limiting cardiomyopathy and heart failure. Here we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part through blunted activity of Electron Transport System Complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial Damage-Associated Molecular Patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations but this lesion was reversed by expression of a phosphomimetic STAT3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trms anti-cancer efficacy.

physiology↗

bioRxiv2020

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

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 ROR in the "staggerer" (RORsg/sg) mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. The mechanisms underlying these observations have not been defined. Here we present evidence that ROR regulates cardiomyocyte mitophagy using pharmacological and genetic gain- and loss-of-function tools, including a novel cardiomyocyte-specific ROR knockout mouse. Cardiomyocyte ROR is upregulated by hypoxia and the loss of ROR blunts hypoxia-induced mitophagy and broadly compromises mitochondrial function. We show that ROR is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that increased expression of ROR increases caveolin-3 abundance and enhances mitophagy. Knockdown of ROR impairs cardiomyocyte mitophagy, but this defect can be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for ROR in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying ROR-mediated cardioprotection.

molecular biology↗