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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 Ca²⁺ ([Ca²⁺]_m), but the mechanism by which miR‐181c regulates [Ca²⁺]_m is unknown.

By RNA sequencing and analysis, here we show that hearts from miR‐181c/d^−/− mice overexpress nuclear‐encoded Ca²⁺ regulatory and metabolic pathway genes, suggesting that alterations in miR‐181c and mt‐COX1 perturb mitochondria‐to‐nucleus retrograde signaling and [Ca²⁺]_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 …