Key result
CROT deficiency attenuates aortic stenosis progression by reducing valvular calcification and procalcific extracellular vesicle release.
Why the study?
Calcific aortic valve disease lacks effective therapy, and the role of CROT in mediating its progression through procalcific mitochondria-derived extracellular vesicles is unknown.
Does CROT inhibition reduce mitochondrial extracellular vesicle release and prevent aortic valve calcification in preclinical models?
Does CROT inhibition reduce mitochondrial extracellular vesicle release and prevent aortic valve calcification in preclinical models?
Inhibiting CROT normalizes mitochondrial function, reduces the release of pro-calcific mitochondrial extracellular vesicles, and attenuates aortic valve calcification in preclinical models.
BACKGROUND: Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator of mitochondrial dysfunction and vascular calcification; however, its role in calcific aortic valve disease is unknown. We investigated whether CROT promotes calcific aortic valve disease progression through the release of procalcific mitochondria-derived extracellular vesicles (mitoEVs). METHODS: (aortic valve wire injury, n=23) mice. Disease progression was monitored by echocardiography, and calcification was visualized using OsteoSense680EX imaging. Proteomics revealed alterations in mitochondria-associated proteins following siCROT. Osteogenic medium-induced mitochondrial fragmentation and increased mitoEV release were attenuated by CROT silencing. Immunofluorescence revealed mitoEVs localized to calcified extracellular regions. In vivo, CROT deficiency reduced valvular calcification and attenuated aortic stenosis progression. CONCLUSIONS: Osteogenic stress drives mitochondrial fragmentation and procalcific mitoEV release. CROT inhibition restores mitochondrial homeostasis, reduces mitoEV release and calcification, identifying CROT as a potential therapeutic strategy for calcific aortic valve disease.
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Itagawa et al. (2026) studied Calcific aortic valve disease (n=54). CROT deficiency / silencing vs. Wild-type Crot+/+ / Scrambled siRNA was evaluated on Valvular calcification measured by ex vivo near-infrared fluorescence (OsteoSense680) imaging (p=0.0074). CROT deficiency significantly reduced valvular calcification and attenuated the progression of aortic stenosis in vivo by inhibiting the release of procalcific mitochondria-derived extracellular vesicles.
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