Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury.

BACKGROUND

Traditional Chinese medicine (TCM) has demonstrated significant advantages in the treatment of coronary microvascular injury, offering novel therapeutic strategies for cardiovascular diseases. Among its active compounds, Tanshinone IIA (TS) has been shown to regulate mitochondrial and endoplasmic reticulum (ER) function. However, the precise mechanisms through which TS exerts its effects, particularly via METTL3- and SIRT5-mediated unfolded protein response (UPR) pathways in microvascular endothelial cells (MECs), remain poorly understood.

PURPOSE

This study aims to elucidate the role of SIRT5 and METTL3 in mediating the protective effects of TS on mitochondrial and ER function in MECs, focusing on the UPR pathways.

STUDY DESIGN

Cardiomyocyte-specific knockout and transgenic mice were utilized to investigate the role of SIRT5 and METTL3. MECs from experimental groups were treated with TS, and various cellular functions were analyzed.

METHODS

The study employed confocal microscopy, electron microscopy, JC-1 assay, MTT assay, and molecular docking techniques to assess mitochondrial and ER functions. Key markers, including mitochondrial membrane potential, protein expression (PINK1, Parkin, PERK, CHOP, and Nrf-1), and transcription levels (PGC1-α, TFAM, and ATF5), were quantified. Calcium ion levels and mitochondrial respiratory functions were also evaluated.

RESULTS

TS treatment enhanced mitochondrial stability, restored mitochondrial membrane potential, and regulated calcium overload through METTL3- and SIRT5-mediated UPR pathways. It upregulated protective proteins (PGC1-α, TFAM, and Nrf-1) while reducing oxidative stress and ER stress markers (CHOP, PERK, and ATF5). Molecular docking confirmed a direct interaction between SIRT5 and METTL3. These changes collectively mitigated microvascular endothelial damage and normalized mitochondrial biogenesis.

CONCLUSION

TS exerts protective effects on MECs by stabilizing mitochondrial function, alleviating calcium overload, and modulating UPR signaling via METTL3 and SIRT5.