Free Tubulin Modulates Mitochondrial Membrane Potential in Cancer Cells

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 Dec 17

PMID 21159641

Citations 116

Authors

Eduardo N Maldonado

Jyoti Patnaik

Matthew R Mullins

John J Lemasters

Affiliations

Soon will be listed here.

Abstract

Formation of the mitochondrial membrane potential (ΔΨ) depends on flux of respiratory substrates, ATP, ADP, and Pi through voltage-dependent anion channels (VDAC). As tubulin promotes single-channel closure of VDAC, we hypothesized that tubulin is a dynamic regulator of ΔΨ, which in cultured cancer cells was assessed by confocal microscopy of the potential-indicating fluorophore tetramethylrhodamine methylester (TMRM). Microtubule destabilizers, rotenone, colchicine, and nocodazole, and the microtubule stabilizer paclitaxel increased and decreased cellular free tubulin, respectively, and in parallel decreased and increased ΔΨ. Protein kinase A (PKA) activation by cAMP analogues and glycogen synthase kinase 3β (GSK-3β) inhibition decreased ΔΨ, whereas PKA inhibition hyperpolarized, consistent with reports that PKA and GSK-3β decrease and increase VDAC conductance, respectively. Plasma membrane potential assessed by DiBAC(4)(3) was not altered by any of the treatments. We propose that inhibition of VDAC by free tubulin limits mitochondrial metabolism in cancer cells.

Citing Articles

Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.

Junco M, Ventura C, Santiago Valtierra F, Maldonado E Antioxidants (Basel). 2025; 13(12.

PMID: 39765891 PMC: 11673973. DOI: 10.3390/antiox13121563.

Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the 10+16 mutation.

Starkie D, Arber C, Baker T, Lightwood D, Wray S MAbs. 2024; 16(1):2436102.

PMID: 39665388 PMC: 11790244. DOI: 10.1080/19420862.2024.2436102.

VDAC1-Based Peptides as Potential Modulators of VDAC1 Interactions with Its Partners and as a Therapeutic for Cancer, NASH, and Diabetes.

Shteinfer-Kuzmine A, Santhanam M, Shoshan-Barmatz V Biomolecules. 2024; 14(9).

PMID: 39334905 PMC: 11430116. DOI: 10.3390/biom14091139.

ECM stiffness regulates calcium influx into mitochondria via tubulin and VDAC1 activity.

Kim M, Han K, Choi G, Ahn S, Suh J, Kim T Anim Cells Syst (Seoul). 2024; 28(1):417-427.

PMID: 39220629 PMC: 11363740. DOI: 10.1080/19768354.2024.2393811.

Endophytic fungi as a potential source of anti-cancer drug.

Sonowal S, Gogoi U, Buragohain K, Nath R Arch Microbiol. 2024; 206(3):122.

PMID: 38407579 DOI: 10.1007/s00203-024-03829-4.

References

Rostovtseva T, Antonsson B, Suzuki M, Youle R, Colombini M, Bezrukov S . Bid, but not Bax, regulates VDAC channels. J Biol Chem. 2004; 279(14):13575-83. DOI: 10.1074/jbc.M310593200. View

Tan W, Colombini M . VDAC closure increases calcium ion flux. Biochim Biophys Acta. 2007; 1768(10):2510-5. PMC: 2220155. DOI: 10.1016/j.bbamem.2007.06.002. View

Liu M, Torgrimson A, Colombini M . Characterization and partial purification of the VDAC-channel-modulating protein from calf liver mitochondria. Biochim Biophys Acta. 1994; 1185(2):203-12. DOI: 10.1016/0005-2728(94)90211-9. View

Mannella C, Forte M, Colombini M . Toward the molecular structure of the mitochondrial channel, VDAC. J Bioenerg Biomembr. 1992; 24(1):7-19. DOI: 10.1007/BF00769525. View

Nieminen A, Byrne A, Herman B, Lemasters J . Mitochondrial permeability transition in hepatocytes induced by t-BuOOH: NAD(P)H and reactive oxygen species. Am J Physiol. 1997; 272(4 Pt 1):C1286-94. DOI: 10.1152/ajpcell.1997.272.4.C1286. View

Hodge T, Colombini M . Regulation of metabolite flux through voltage-gating of VDAC channels. J Membr Biol. 1997; 157(3):271-9. DOI: 10.1007/s002329900235. View

Harvey A, Kind K, Thompson J . REDOX regulation of early embryo development. Reproduction. 2002; 123(4):479-86. DOI: 10.1530/rep.0.1230479. View

Brinkley B, Barham S, Barranco S, Fuller G . Rotenone inhibition of spindle microtubule assembly in mammalian cells. Exp Cell Res. 1974; 85(1):41-6. DOI: 10.1016/0014-4827(74)90210-9. View

DAVIES S, Reddy H, Caivano M, Cohen P . Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000; 351(Pt 1):95-105. PMC: 1221339. DOI: 10.1042/0264-6021:3510095. View

10.

Holmuhamedov E, Lemasters J . Ethanol exposure decreases mitochondrial outer membrane permeability in cultured rat hepatocytes. Arch Biochem Biophys. 2008; 481(2):226-33. PMC: 2656607. DOI: 10.1016/j.abb.2008.10.036. View

11.

Horwitz S . Mechanism of action of taxol. Trends Pharmacol Sci. 1992; 13(4):134-6. DOI: 10.1016/0165-6147(92)90048-b. View

12.

Rostovtseva T, Colombini M . VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys J. 1997; 72(5):1954-62. PMC: 1184392. DOI: 10.1016/S0006-3495(97)78841-6. View

13.

Marshall L, Himes R . Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta. 1978; 543(4):590-4. DOI: 10.1016/0304-4165(78)90315-x. View

14.

Bera A, Ghosh S, Das S . Mitochondrial VDAC can be phosphorylated by cyclic AMP-dependent protein kinase. Biochem Biophys Res Commun. 1995; 209(1):213-7. DOI: 10.1006/bbrc.1995.1491. View

15.

Gambhir S . Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer. 2002; 2(9):683-93. DOI: 10.1038/nrc882. View

16.

Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C . Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res. 2008; 103(9):983-91. PMC: 2661871. DOI: 10.1161/CIRCRESAHA.108.178970. View

17.

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View

18.

Ehrenberg B, Montana V, Wei M, Wuskell J, Loew L . Membrane potential can be determined in individual cells from the nernstian distribution of cationic dyes. Biophys J. 1988; 53(5):785-94. PMC: 1330255. DOI: 10.1016/S0006-3495(88)83158-8. View

19.

Rousset B . Interaction of tubulin with rat liver mitochondria. J Biol Chem. 1982; 257(12):7092-9. View

20.

Xu X, Forbes J, Colombini M . Actin modulates the gating of Neurospora crassa VDAC. J Membr Biol. 2001; 180(1):73-81. DOI: 10.1007/s002320010060. View