TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells.
Transforming growth factor beta1 (TGF beta1) is a well-characterized cytokine that suppresses epithelial cell growth. We report here that TGF beta1 arrested lung epithelial Mv1Lu cells at G1 phase of the cell cycle with acquisition of senescent phenotypes in the presence of 10% serum, whereas it gradually induced apoptosis with lower concentrations of serum. The senescent arrest was accompanied by prolonged generation of reactive oxygen species (ROS) and persistent disruption of mitochondrial membrane potential (DeltaPsim). We demonstrated that the sustained ROS overproduction was derived from mitochondrial respiratory defect via decreased complex IV activity and was involved in the arrest. Moreover, we verified that hepatocyte growth factor released Mv1Lu cells from the arrest by protecting mitochondrial respiration, thereby preventing both the DeltaPsim disruption and the ROS generation. Our present results suggest the TGF beta1-induced senescent arrest as another plausible mechanism to suppress cellular growth in vivo and provide a new biochemical association between the mitochondrial functional defects and the cytokine-induced senescent arrest, emphasizing the importance of maintenance of mitochondrial function in cellular protection from the arrest.
Yoon
Young-Sil
YS
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, San 5, Wonchon-dong, Youngtong-gu, Suwon 443-721, South Korea.
Lee
Jae-Ho
JH
Hwang
Sung-Chul
SC
Choi
Kyeong Sook
KS
Yoon
Gyesoon
G
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D008168:Lung; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003576:Electron Transport Complex IV