Pharmacological activation of mitophagy prevents calcific aortic valve disease by targeting dysregulated mitochondrial-to-nuclear communication
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Background and Aims
Calcific aortic valve disease (CAVD) lacks pharmacologic therapy. Mitophagy impairment contributes to various degenerative diseases, but whether it occurs in calcified aortic valves and during human valvular interstitial cell (hVIC) osteogenic differentiation remains unknown. We therefore investigated the role of mitophagy in CAVD and whether its pharmacological treatment prevents disease progression.
Methods
Single-cell RNA sequencing (scRNA-seq) was performed on human aortic valves and hVICs. TJ0113, a novel orally available mitophagy activator from our previous screening, was tested in two CAVD mouse models. Multi-omics analyses and functional rescue experiments were performed to elucidate the mechanism.
Results
Mitophagy was impaired in calcified human aortic valves and during hVIC osteogenic differentiation. TJ0113 activated MCL1-mediated mitophagy and attenuated disease progression in vitro and in vivo. Mechanistically, the mitophagy receptor MCL1 anchors a fraction of PRMT3 on mitochondria. During osteogenic differentiation, a dysregulated mitochondrial-to-nuclear communication is initiated by the increased release of PRMT3 into the cytosol, where it interacts with BACH1 and impairs BACH1 nuclear translocation. This leads to a widespread loss of BACH1 genomic occupancy, relieving BACH1-mediated transcriptional repression of the pro-osteogenic factor PARM1 and promoting hVIC osteogenic differentiation. Mitophagy activation by TJ0113 restored MCL1-PRMT3 binding and reversed these alterations.
Conclusions
Mitophagy impairment drives CAVD through dysregulated mitochondrial-to-nuclear communication mediated by the MCL1-PRMT3-BACH1-PARM1 axis. Pharmacological mitophagy activation by TJ0113 corrects this communication and attenuates disease progression, representing a promising therapeutic strategy for CAVD.
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Pharmacological activation of mitophagy prevents calcific aortic valve disease by targeting dysregulated mitochondrial-to-nuclear communication https://www.biorxiv.org/content/10.64898/2026.10.31.763012v1
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Pharmacological activation of mitophagy prevents calcific aortic valve disease by targeting dysregulated mitochondrial-to-nuclear communication https://www.biorxiv.org/content/10.64898/2026.10.31.763012v1
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