Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism.

Abstract

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.

• Authors: Wu Yin, Xiang Li, Su Feng, Wei Cheng, Bo Tang, Yi-Lin Shi, Zi-Chun Hua
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 78 Issue 2 Pg. 191-202 (Jul 15 2009) ISSN: 1873-2968 [Electronic] England
• PMID: 19442964 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Rotenone
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cell Membrane (drug effects, enzymology)
• Cell Survival (drug effects, physiology)
• Humans
• Intracellular Membranes (drug effects, enzymology, metabolism)
• Jurkat Cells
• Leukemia, T-Cell (enzymology, pathology)
• Mice
• Mice, Transgenic
• Mitochondrial Membranes (drug effects, enzymology, pathology)
• Rotenone (toxicity)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors, metabolism)
• T-Lymphocytes (cytology, drug effects, enzymology)
• U937 Cells