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 analyze 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 increased 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. Conclusions Our data suggest that the Calcific Aortic Valve Stenosis 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 revert quite all pathological phenotypes. Translational perspective The findings from this study provide evidence for new molecular targets involving mitochondrial quality control mechanisms becoming dysregulated in CAVS. These pathways should be considered as amenable for a combination of new therapies in humans for three reasons: i) no pharmacological treatments are still available to slow down the development of advanced CAVS, ii) being calcification a recurring pathway and iii) the targets proposed are druggable by existing drugs used in the clinic for different purposes. This work also suggests a serum biomarker to be highly related to the stage of disease and the calcification grade of the valve.