Tubulin Is an Inherent Component of Mitochondrial Membranes That Interacts with the Voltage-dependent Anion Channel

Carré, Manon; André, Nicolas; Carles, Gérard; Borghi, H.; Brichese, Laetitia; Briand, Claudette; Braguer, Diane

doi:10.1074/jbc.m203834200

Cited by 253 publications

(211 citation statements)

References 33 publications

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“…However, this original view seems now incorrect, because TUBB3 expression has recently been observed in other tissues and particularly in the mitochondrial membrane where it exerts an unknown function (4). Several reports indicate that an increase in the relative abundance of TUBB3 isoform destabilizes the microtubules and correlates with drug resistance (5 -8).…”

Section: Introductionmentioning

confidence: 99%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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Class III B-tubulin (TUBB3) has been discovered as a marker of drug resistance in human cancer. To get insights into the mechanisms by which this protein is involved in drug resistance, we analyzed TUBB3 in a panel of drug-sensitive and drug-resistant cell lines. We identified two main different isoforms of TUBB3 having a specific electrophoretic profile. We showed that the apparently higher molecular weight isoform is glycosylated and phosphorylated and it is localized in the cytoskeleton. The apparently lower molecular weight isoform is instead found exclusively in mitochondria. We observed that levels of phosphorylation and glycosylation of TUBB3 are associated with the resistant phenotype and compartmentalization into cytoskeleton. By two-dimensional nonreduced/reduced SDS-PAGE analysis, we also found that TUBB3 protein in vivo forms protein complexes through intermolecular disulfide bridges. Through TUBB3 immunoprecipitation, we isolated protein species able to interact with TUBB3. Following trypsin digestion, these proteins were characterized by mass spectrometry analysis. Functional analysis revealed that these proteins are involved in adaptation to oxidative stress and glucose deprivation, thereby suggesting that TUBB3 is a survival factor able to directly contribute to drug resistance. Moreover, glycosylation of TUBB3 could represent an attractive pathway whose inhibition could hamper cytoskeletal compartmentalization and TUBB3 function.

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Section: Introductionmentioning

confidence: 99%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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“…Tubulin dimers bind to VDAC channels, both in artificial lipid bilayers and in isolated mitochondria [Carre et al, 2002;. When VDAC channels are incorporated into artificial lipid bilayers, nanomolar concentrations of tubulin cause VDAC closure at very low potentials ( 10 mV) .…”

Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacmentioning

confidence: 99%

“…It is not yet known whether a change in potential across the outer mitochondrial membrane is a relevant physiological regulator of small molecule transport in and out of mitochondria. Binding of tubulin or HK to VDAC regulates channel open/closed states as discussed next.Tubulin dimers bind to VDAC channels, both in artificial lipid bilayers and in isolated mitochondria [Carre et al, 2002;. When VDAC channels are incorporated into artificial lipid bilayers, nanomolar concentrations of tubulin cause VDAC closure at very low potentials ( 10 mV) .…”

mentioning

confidence: 99%

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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“…83,84 Decreased growth factor signaling through Akt with resulting increased GSK3␤ activation leads to dissociation of hexokinase from VDAC and increased probability of mitochondrial permeability transition and apoptosis, and it can also increase sensitivity to chemotherapeutic agents. 85 Microtubule-targeted chemotherapeutic agents also favor mitochondrial permeability pore transition by modulating tubulin-VDAC interaction, 86 and some HAARTs may affect the mPTP by binding to ANT. Swollen and vacuolated mitochondria have been observed clinically and in animal models of diabetes and chemotherapyinduced neuropathic pain.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Recent observations also suggest that olesoxime targets tubulin, which has been shown to be in close association with VDAC in mitochondria. 86,132 The current working hypothesis on the mechanism of action of olesoxime is in favor of a tight regulation of mitochondrial pore opening through interactions with these proteins.…”

Section: Acetyl-l-carnitine: Mechanism Efficacy In Animal Models Andmentioning

confidence: 99%

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

Bordet

Pruss

2009

Neurotherapeutics

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Summary:Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long-lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders.

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Tubulin Is an Inherent Component of Mitochondrial Membranes That Interacts with the Voltage-dependent Anion Channel

Cited by 253 publications

References 33 publications

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

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

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

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