Mitophagy induced by endoplasmic reticulum stress in heart is modulated by the sirtuin 1.

Introduction Disruption of Endoplasmic Reticulum (ER) homeostasis, a condition referred to as ER stress, has been implicated in many cardiovascular diseases. In response to ER stress, several beneficial physiological adaptive response of the cell are triggered, such as autophagy. Mitophagy is a dynamic process responsible for the degradation of mitochondria by the lysosomal pathway. However, severe ER stress triggers autophagic cell death/apoptosis and exacerbates cardiac dysfunction. Objective In this context, we chose to study the role of sirtuin 1 (Sirt1), a deacetylase activated in response to many cardiac stresses to promote cell survival, as modulator of ER stress–induced mitophagy in the heart. Method In our study, H9c2 cells (rat cardiomyoblasts) were treated with the well-known ER stress inducer tunicamycin (TN, 10 μg/mL) and showed time course an increase of ER stress marker (GRP78, CHOP) and autophagy (LC3-II and Cyto-ID ® ) markers. By flow cytometry and western blot, we studied the role of SIRT1 in ER stress-induced mitophagy. In vivo, we analysed the effect of TN injection (2 mg/kg) in inductible Sirt1 knock out mice and we observed mitophagy by electron microscopy. Results We have shown that TN induces ER stress and autophagy in H9c2 cells. Moreover inhibition/extinction of Sirt1 by EX-527/siRNA decreased ER stress-induced mitophagy to a level similar to that of the two well known autophagy inhibitors, 3-methyl adenine and chloroquine. In vivo, TN injection triggered a sustained ER stress response who amplifies cardiac dysfunction in inductible Sirt1 knock out mice and we observed that TN induced mitophagy. Conclusion Our results show that activation of Sirt1 promotes the induction of mitophagy in response to ER stress, protecting the cardiac cells from cell death. Sirt1 thus appears as an interesting therapeutic target to modulate adaptive autophagy in ER stress-associated cardiac pathologies. [ABSTRACT FROM AUTHOR]