Mitochondrial Dysfunction and Ca2+ Overload Contributes to Hesperidin Induced Paraptosis in Hepatoblastoma Cells, HepG2

Abstract

Paraptosis is a programmed cell death which is morphologically and biochemically different from apoptosis. In this study, we have investigated the role of Ca2+ in hesperidin-induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca2+ level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol-1,4,5-triphosphate receptor (IP3R) and ryanodine receptor also block the mitochondrial Ca2+ accumulation suggesting that the release of Ca2+ from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca2+ level. Pretreatment with ruthenium red (RuRed), a Ca2+ uniporter inhibitor inhibited the hesperidin-induced mitochondrial Ca2+ overload, swelling of mitochondria, and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca2+ influxes act upstream of ROS and mitochondrial superoxide production. The increased ROS production further leads to mitochondrial membrane loss in hesperidin treated HepG2 cells. Taken together our results show that IP3R and ryanodine receptor mediated release of Ca2+ from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin-induced paraptosis in HepG2 cells. (c) 2015 Wiley Periodicals, Inc.