Mitochondrial Dysfunction and Ca(2+) Overload Contributes to Hesperidin Induced Paraptosis in Hepatoblastoma Cells, HepG2.
Paraptosis is a programmed cell death which is morphologically and biochemically different from apoptosis. In this study, we have investigated the role of Ca(2+) in hesperidin-induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca(2+) level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol-1,4,5-triphosphate receptor (IP3 R) and ryanodine receptor also block the mitochondrial Ca(2+) accumulation suggesting that the release of Ca(2+) from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca(2+) level. Pretreatment with ruthenium red (RuRed), a Ca(2+) uniporter inhibitor inhibited the hesperidin-induced mitochondrial Ca(2+) overload, swelling of mitochondria, and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca(2+) 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 IP3 R and ryanodine receptor mediated release of Ca(2+) from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin-induced paraptosis in HepG2 cells.
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Silvia
S
Yumnam
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Gyeong Eun
GE
Hong
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Suchismita
S
Raha
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Venu Venkatarame Gowda
VV
Saralamma
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Ho Jeong
HJ
Lee
Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea.
Won-Sup
WS
Lee
Department of Nursing Science, International University of Korea, Jinju, Republic of Korea.
Eun-Hee
EH
Kim
Research Institute of Life Science, College of Veterinary Medicine (BK21 plus project), Gyeongsang National University, Gazwa, Jinju, Republic of Korea.
Gon Sup
GS
Kim
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006569:Hesperidin / Q000494:pharmacology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008933:Mitochondrial Swelling / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D013481:Superoxides; D006569:Hesperidin; D002118:Calcium