| First Author | Banavath HN | Year | 2019 |
| Journal | J Am Heart Assoc | Volume | 8 |
| Issue | 24 | Pages | e012919 |
| PubMed ID | 31801413 | Mgi Jnum | J:299355 |
| Mgi Id | MGI:6491997 | Doi | 10.1161/JAHA.119.012919 |
| Citation | Banavath HN, et al. (2019) miR-181c Activates Mitochondrial Calcium Uptake by Regulating MICU1 in the Heart. J Am Heart Assoc 8(24):e012919 |
| abstractText | Background Translocation of miR-181c into cardiac mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d(-/-) hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca(2+) ([Ca(2+)]m), but the mechanism by which miR-181c regulates [Ca(2+)]m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d(-/-) mice overexpress nuclear-encoded Ca(2+) regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca(2+)]m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR-181c/d(-/-) hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by chromatin immunoprecipitation-quantitative polymerase chain reaction and higher expression of MICU1 was found in the miR-181c/d(-/-) hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca(2+)]m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d(-/-) heart by lentiviral expression of a short-hairpin RNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d(-/-) neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU1 in ischemic injury. Conclusions miR-181c regulates mt-COX1, which in turn regulates MICU1 expression through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca(2+)]m through the upregulation of MICU1. |
