Free Tubulin Modulates Mitochondrial Membrane Potential in Cancer Cells

Maldonado, Eduardo N.; Patnaik, Jyoti; Mullins, Matthew R.; Lemasters, John J.

doi:10.1158/0008-5472.can-10-2429

Cited by 196 publications

(247 citation statements)

References 49 publications

(56 reference statements)

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“…Conversely, treatment of cells with pacilitaxel, to drive most or all tubulins into MT polymer, caused mitochondrial inner membrane hyperpolarization [Maldonado et al, 2010], consistent with the idea that VDACs in the outer membrane remain in an open state longer, or that more channels are opened, when the soluble tubulin concentration is reduced. Curiously, this hyperpolarization was only observed in cancer derived cell lines and not in freshly isolated rat hepatocytes [Maldonado et al, 2010]. In separate studies, hyperpolarization of the inner mitochondrial membrane has been identified as an early step in apoptosis [Nagy et al, 2007].…”

Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacsupporting

confidence: 73%

“…Increased soluble tubulin binding to VDAC channels should also prevent ATP from entering the cytoplasm. Conversely, treatment of cells with pacilitaxel, to drive most or all tubulins into MT polymer, caused mitochondrial inner membrane hyperpolarization [Maldonado et al, 2010], consistent with the idea that VDACs in the outer membrane remain in an open state longer, or that more channels are opened, when the soluble tubulin concentration is reduced. Curiously, this hyperpolarization was only observed in cancer derived cell lines and not in freshly isolated rat hepatocytes [Maldonado et al, 2010].…”

supporting

confidence: 73%

“…To date, this question has been addressed using a dye to measure mitochondrial inner membrane potential in cells treated with MT-targeting drugs to shift tubulin distribution into essentially all soluble dimers or all into polymer [Maldonado et al, 2010]. MT depolymerization with colchicine or nocodazole reduced mitochondrial inner membrane potential [Maldonado et al, 2010;Sheldon et al, 2011].…”

Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacmentioning

confidence: 99%

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Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

et al. 2012

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Microtubules (MTs) or their subunits, tubulin dimers, interact with multiple components that contribute to intracellular metabolic pathways. MTs are required for insulin-dependent transport of glucose transporter 4 to the plasma membrane, they bind most glycolytic enzymes and are required for translation of the mRNA encoding hypoxia inducible factor-1a. Tubulin dimers bind the voltage-dependent anion channel of the mitochondrial outer membrane; this channel functions in metabolite transport in and out of mitochondria. We hypothesize that tubulin partitioning between dimer and polymer pools regulates multiple steps in metabolism, where metabolic output is greatest when both tubulin dimers and MT polymers are present and reduced by drug treatments that disrupt this normal balance. Experimental evidence from these drug-induced changes in tubulin dimer/polymer partitioning supports our model for several metabolic steps. Signal transduction pathways that stabilize or destabilize MTs can shift the normal ratio between unpolymerized and polymerized tubulin dimers, and one downstream consequence of this shift in tubulin partitioning could be a change in metabolic output. V C 2012 Wiley Periodicals, Inc Key Words: glycolysis, oxidative phosphorylation, glucose transport, voltage-dependent anion channel, tubulin IntroductionT he microtubule (MT) cytoskeleton has well-characterized roles in cell polarity, motility, mitosis, and vesicle traffic. The dynamic turnover of MTs is critical to most of these processes, allowing the cell to reorganize an array of MTs rapidly for specific functions. Here we posit an additional role for MTs in regulating metabolic processes and propose that metabolism is greatest when both MTs and their tubulin subunits are present in cells. Disruption of this normal balance, to either inhibit or promote MT polymerization, is expected to decrease metabolic output. Our hypothesis predicts that chemotherapies that stabilize or destabilize MTs will significantly impact metabolic pathways and reduce ATP levels. Importantly, even a small decrease in ATP production can slow cell proliferation. For example, a 19% decrease in ATP production was sufficient to induce senescence in mouse embryo fibroblasts [Kondoh et al., 2005], indicating that even a relatively small contribution of the MT cytoskeleton to metabolic output could have a significant impact on cell fate.The metabolic components and pathways we consider here include glucose transporters (GLUTs), glycolysis, the pentose phosphate pathway (PPP), and mitochondrial oxidative phosphorylation. Glucose enters cells through glucose transporters called GLUTs; the concentration of GLUTs at the plasma membrane can be regulated by insulin and requires trafficking of GLUT-containing vesicles along MTs to reach the plasma membrane. Within the cytoplasm, glucose is broken down to pyruvate during glycolysis, yielding ATP and NADH. Several intermediate products of glucose breakdown, including glucose-6-phosphate (G6P) and glyceraldehyde-3-phosphate (GAP), can also ...

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Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacsupporting

confidence: 73%

supporting

confidence: 73%

Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacmentioning

confidence: 99%

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Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

et al. 2012

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“…Some studies proposed that free tubulin can modulate MMP, VDAC and hence, mitochondrial outer membrane permeability in cancer cells (Maldonado et al, 2010;Rostovtseva and Bezrukov, 2012). In addition, Sheldon's team discovered that phosphorylation of VDAC governs its interaction with tubulin (Sheldon et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Xue

Zhang

et al. 2013

Molecules and Cells

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Hypoxia-induced microtubule disruption and mitochondrial permeability transition (mPT) are crucial events leading to fatal cell damage and recent studies showed that microtubules (MTs) are involved in the modulation of mitochondrial function. Dynein light chain Tctex-type 1 (DYNLT1) is thought to be associated with MTs and mitochondria. Previously we demonstrated that DYNLT1 knockdown aggravates hypoxia-induced mitochondrial permeabilization, which indicates a role of DYNLT1 in hypoxic cytoprotection. But the underlying regulatory mechanism of DYNLT1 remains illusive. Here we aimed to investigate the phosphorylation alteration of DYNLT1 at serine 82 (S82) in hypoxia (1% O 2 ). We therefore constructed recombinant adenoviruses to generate S82E and S82A mutants, used to transfect H9c2 and HeLa cell lines. Development of hypoxia-induced mPT (MMP examining, Cyt c release and mPT pore opening assay), hypoxic energy metabolism (cellular viability and ATP quantification), and stability of MTs were examined. Our results showed that phosph-S82 (S82-P) expression was increased in early hypoxia; S82E mutation (phosphomimic) aggravated mitochondrial damage, elevated the free tubulin in cytoplasm and decreased the cellular viability; S82A mutation (dephosphomimic) seemed to diminish the hypoxia-induced injury. These data suggest that DYNLT1 phosphorylation at S82 is involved in MTs and mitochondria regulation, and their interaction and cooperation contribute to the cellular hypoxic tolerance. Thus, we provide new insights into a DYNLT1 mechanism in stabilizing MTs and mitochondria, and propose a potential therapeutic target for hypoxia cytoprotective studies.

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“…Moreover, mitochondria of cancer cells maintain mitochondrial membrane potential (⌬⌿) through respiration and ATP hydrolysis as predicted by chemiosmotic theory (9). Thus, suppression of mitochondrial metabolism in tumor cells is not a deficit of mitochondrial function but rather a physiological adaptation that remains incompletely understood.…”

mentioning

confidence: 99%

Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells

Maldonado

Sheldon

DeHart

et al. 2013

Journal of Biological Chemistry

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Free Tubulin Modulates Mitochondrial Membrane Potential in Cancer Cells

Cited by 196 publications

References 49 publications

Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells

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