Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Abstract

Cardiomyocyte apoptosis is a major process in pathogenesis of a number of heart diseases, including ischemic heart diseases and cardiac failure. Ensuring survival of cardiac cells by blocking apoptotic events is an important strategy to improve cardiac function. Although the role of ER disruption in inducing apoptosis has been demonstrated, we do not yet fully understand how it influences the mitochondrial apoptotic machinery in cardiac cell models. Recent investigations have provided evidences that the prosurvival protein HCLS1-associated protein X-1 (Hax1) protein is intimately associated with the pathogenesis of heart disease, mitochondrial biology, and protection from apoptotic cell death. To study the role of Hax1 upon ER stress induction, Hax1 was overexpressed in cardiac cells subjected to ER stress, and cell death parameters as well as mitochondrial alterations were examined. Our results demonstrated that the Hax1 is significantly downregulated in cardiac cells upon ER stress induction. Moreover, overexpression of Hax1 protected from apoptotic events triggered by Tunicamycin-induced ER stress. Upon treatment with Tunicamycin, Hax1 protected from mitochondrial fission, downregulation of mitofusins 1 and 2 (MFN1 and MFN2), loss of mitochondrial membrane potential (ΔΨm), production of reactive oxygen species (ROS) and apoptotic cell death. Taken together, our results suggest that Hax1 inhibits ER stress-induced apoptosis at both the pre- and post-mitochondrial levels. These findings may offer an opportunity to develop new agents that inhibit cell death in the diseased heart.

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

“…9 Recently, Abdelwahid et al demonstrated HAX1-mediated cell survival by protection from multiple apoptotic signals in a cardiomyocyte cell line. 63 We also observed deregulation of genes involved in a multitude of apoptotic processes, such as PARL, FAIM2, and TMBIM6, suggesting that the role of HAX1 and HCLS1 in apoptosis of myeloid cells may be another key function in the Kostmann disease genetic network. In fact, we validated decreased mitochondrial membrane potential and increased apoptosis in those cells.…”

Mitofusin 2 inhibits bladder cancer cell proliferation and invasion via the Wnt/β‑catenin pathway

“…Overexpression of MFN2 induces the formation of mitochondrial networks and may involve a major rearrangement of the coiled coil domains (16). It is also involved in the clearance of damaged mitochondria via selective autophagy and the regulation of the unfolded protein response upon estrogen receptor stress (17).…”

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

“…Hax1 is significantly downregulated in cardiac cells upon ER stress, which also resulted in a disrupted mitochondrial morphology, Mfn2 downregulation, and ROS production. Importantly, overexpression of Hax1 protected against ER stress-induced apoptosis and mitochondrial changes, suggesting that Hax1 could be a critical modulator in the cross talk between the ER and mitochondria [52]. The tumor suppressor protein p53 is also an inducer of apoptosis ( Figure 2).…”