Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favouring cell death and the severity of disease

Aims In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS. Methods and results This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the pathologic group is aged with significant alterations in biogenesis and mitophagy pathways. We are also reporting an updated view about autophagy accompanying the calcification process and advanced stages of the disease. We provided evidence for a rapamycin-based therapeutic strategy to revert the calcified phenotype to the wild type one. Conclusion Our data suggest that the CAVS phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Thus, boosting autophagy and mitophagy from short- to long-term reverts quite all pathological phenotypes.

Automated summary

This observational study aims to establish the trend of autophagy in CAVS patients, analyze the involvement of other determinants impacting mitochondrial quality control mechanisms, and explore potential pharmacological interventions. The results show deficiencies in mitochondrial respiration, ATP production, and alterations in biogenesis and mitophagy pathways in the calcified valves, suggesting a rapamycin-based therapeutic strategy to revert pathological phenotypes. Boosting autophagy and mitophagy could potentially counteract cell death and sustain cell functions in the long term.