Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells REGULATION BY FREE TUBULIN AND ERASTIN

被引：202

作者：

Maldonado, Eduardo N. ^{[2
,4
]}

Sheldon, Kely L. ^{[5
,6
]}

DeHart, David N. ^{[2
]}

Patnaik, Jyoti ^{[2
]}

Manevich, Yefim

Townsend, Danyelle M. ^{[2
,4
]}

Bezrukov, Sergey M. ^{[5
]}

Rostovtseva, Tatiana K. ^{[5
]}

Lemasters, John J. ^{[1
,2
,3
,4
]}

机构：

[1] Med Univ S Carolina, Ctr Cell Death Injury & Regenerat, Charleston, SC 29425 USA

[2] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA

[3] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[4] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA

[5] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA

[6] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstein Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2013年 / 288卷 / 17期

基金：

美国国家卫生研究院;

关键词：

OUTER-MEMBRANE; VDAC CHANNELS; WARBURG; ADP; PERMEABILITY; RESPIRATION; GLYCOLYSIS; ACTIVATION; ISOFORMS; RELEASE;

D O I：

10.1074/jbc.M112.433847

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Respiratory substrates and adenine nucleotides cross the mitochondrial outer membrane through the voltage-dependent anion channel (VDAC), comprising three isoforms - VDAC1, 2, and 3. We characterized the role of individual isoforms in mitochondrial metabolism by HepG2 human hepatoma cells using siRNA. With VDAC3 to the greatest extent, all VDAC isoforms contributed to the maintenance of mitochondrial membrane potential, but only VDAC3 knockdown decreased ATP, ADP, NAD(P)H, and mitochondrial redox state. Cells expressing predominantly VDAC3 were least sensitive to depolarization induced by increased free tubulin. In planar lipid bilayers, free tubulin inhibited VDAC1 and VDAC2 but not VDAC3. Erastin, a compound that interacts with VDAC, blocked and reversed mitochondrial depolarization after microtubule destabilizers in intact cells and antagonized tubulin-induced VDAC blockage in planar bilayers. In conclusion, free tubulin inhibits VDAC1/2 and limits mitochondrial metabolism in HepG2 cells, contributing to the Warburg phenomenon. Reversal of tubulin-VDAC interaction by erastin antagonizes Warburg metabolism and restores oxidative mitochondrial metabolism.

引用

页码：11920 / 11929

页数：10

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