A tanshinone IIA derivative designed to target mitochondria inhibit myocardial ischemia/reperfusion injury in vivo in a GUF1 dependent- pathway

Mitochondrial dysfunction is the common pathological basis of myocardial ischemia/reperfusion (I/R) injury, which induces an intriguing study on mitochondrial-targeting compounds to treat mitochondrial dysfunction related diseases. Herein, a novel mitochondrial targeting compound Tan-TPP was synthesized based on tanshinone IIA (Tan), an active constituent of Chinese medicine salvia miltiorrhiza. We employed TMT labeled quantitative mass spectrometry, bioinformatics analysis, gene knockdown and overexpression assays to explore the regulation mechanism of Tan-TPP on attenuating myocardial I/R injury. Intriguingly, Tan-TPP could accumulate in mitochondria and significantly attenuate myocardial H/R injury at cellular level and I/R injury in vivo. It can regulate the expression of mitochondrial protein GUF1, thereby reducing SDHA expression level to attenuate oxidative injury. Consequently, this study expands our understanding on the mechanism of mitochondrial-targeting molecules to attenuate myocardial I/R injury, and it also provides a new strategy to improve the efficacy of Chinese medicine.