miR‐181c Activates Mitochondrial Calcium Uptake by Regulating MICU1 in the Heart

作者：Hemanth N. Banavath, Bárbara Román, Nathan Mackowski, Debjit Biswas, Junaid Afzal, Yohei Nomura, Soroosh Solhjoo, Brian O’Rourke, Mark J. Kohr, Elizabeth Murphy, Charles Steenbergen, Samarjit Das · 发表于：Journal of the American Heart Association · 年份：2019 · DOI：10.1161/jaha.119.012919 · 被引用次数：35 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、MicroRNA in disease regulation

Background Translocation of miR‐181c into cardiac mitochondria downregulates the mitochondrial gene, mt‐ COX 1. 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‐ COX 1 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 MICU 1 was confirmed by chromatin immunoprecipitation‐quantitative polymerase chain reaction and higher expression of MICU 1 was found in the miR‐181c/d −/− hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU 1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR‐181c/ MICU 1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU 1 was knocked down in the miR‐18...