The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy
| العنوان: | The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy |
|---|---|
| المؤلفون: | Hong Soon Kang, Anton M. Jetten, Kevin Gerrish, Amir Aghajanian, Ju Youn Beak, Brian C. Jensen, Seok Jae Hong, Wei Huang, Rishi Deshmukh, Nishi Kadakia |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | HIF-1α, hypoxia-inducible factor-1α, Caveolin 3, PINK1, PTEN-induced putative kinase 1, LC3B-II, microtubule-associated protein light chain beta 3-II, Mitochondrion, Biochemistry, CMKO, cardiomyocyte-specific RORα KO, JC-1, 5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolylcarbocyanine iodide, Mitochondria, Heart, Mice, Mitophagy, OCR, oxygen consumption rate, Myocytes, Cardiac, Cav-3, caveolin-3, mt-Keima, mitochondrial-targeted Keima, shCtrl, scrambled shRNA, Cardioprotection, Gene knockdown, LDH, lactate dehydrogenase, Bnip3, BCL2 interacting protein 3, HRP, horseradish peroxidase, Nuclear Receptor Subfamily 1, Group F, Member 1, shRORα, shRNA against RORα, Cell biology, ChIP, chromatin immunoprecipitation, BFA1, bafilomycin A1, SDH, succinate dehydrogenase, NRVMs, neonatal rat ventricular myocytes, qRT-PCR, quantitative RT-PCR, Research Article, caveolin-3, mPTP, mitochondrial permeability transition pore, cardiomyocyte mitochondrial physiology, Biology, ROS, reactive oxygen species, Downregulation and upregulation, Animals, TEM, transmission electron microscopy, Molecular Biology, ROR, retinoic acid–related orphan nuclear receptor, Ang II, angiotensin II, hypoxia, Autophagy, Cell Biology, RAR-related orphan receptor alpha (ROR-alpha), Nuclear receptor, Hsp60, heat shock protein 60, PFA, paraformaldehyde |
| الوصف: | 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 RORα 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 RORα regulates cardiomyocyte mitophagy to preserve mitochondrial abundance and function. We found that cardiomyocyte mitochondria in staggerer mice with lack of functional RORα were less numerous and exhibited fewer mitophagy events than those in WT controls. The hearts of our novel cardiomyocyte-specific RORα 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 RORα were upregulated by hypoxia, a classical inducer of mitophagy. The loss of RORα blunted mitophagy and broadly compromised mitochondrial function in normoxic and hypoxic conditions in vivo and in vitro. We also show that RORα is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that enhanced expression of RORα increases caveolin-3 abundance and enhances mitophagy. Finally, knockdown of RORα 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 RORα in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying RORα-mediated cardioprotection. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::47cc243bde3123b1ebf3e9dc15c170f2Test http://europepmc.org/articles/PMC8626585Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....47cc243bde3123b1ebf3e9dc15c170f2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
|---|