Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism.
Na,K-ATPase is a ubiquitous transmembrane protein that regulates and maintains the intracellular Na(+) and K(+) gradient necessary for cell homeostasis. Recently, the importance of this pump in external stimuli-induced leukemia cell apoptosis has been increasingly appreciated, however, the exact role of Na,K-ATPase in mitochondrial apoptotic pathway still remains little understood. In this study, we found mitochondrial toxin rotenone caused a rapid mitochondrial membrane potential (MMP) collapse in Jurkat cells followed by plasma membrane depolarization (PMP). Similar results were also obtained in human U937 cells and non-cancerous mouse primary T cells. Rotenone-induced PMP depolarization occurred before apoptosis and well correlated with Na,K-ATPase impairment. To understand the mechanisms, Jurkat cells with mtDNA depletion and catalase overexpression were used. The results demonstrated that both PMP depolarization and Na,K-ATPase impairment induced by rotenone were regulated by mitochondrial H(2)O(2) and Bcl-2. Finally, Na,K-ATPase suppression by ouabain greatly accelerated and enhanced mitochondrial toxins-induced cells apoptosis in Jurkat, U937 and primary T cells. In sum, by using leukemia cells and mouse primary T cells, we confirmed that mitochondria-to-Na,K-ATPase and PMP depolarization might represent a novel mechanism for mitochondria to amplify death signals in the initiation stage of cells apoptosis induced by mitochondrial toxins.
Yin
Wu
W
The State Key Lab of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, 22# HanKou Rd., Nanjing 210093, PR China.
Li
Xiang
X
Feng
Su
S
Cheng
Wei
W
Tang
Bo
B
Shi
Yi-Lin
YL
Hua
Zi-Chun
ZC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D012402:Rotenone / Q000633:toxicity; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020298:U937 Cells
D012402:Rotenone; D000254:Sodium-Potassium-Exchanging ATPase