Hexokinase-Mitochondria Interaction Mediated by Akt Is Required to Inhibit Apoptosis in the Presence or Absence of Bax and Bak

Majewski, Nathan; Nogueira, Véronique; Bhaskar, Prashanth T.; Coy, Platina E.; Skeen, Jennifer; Gottlob, Kathrin; Chandel, Navdeep S.; Thompson, Craig B.; Robey, R. Brooks; Hay, Nissim

doi:10.1016/j.molcel.2004.11.014

Cited by 582 publications

(530 citation statements)

References 51 publications

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“…This peptide has been previously shown to force dissociation of HK-II from mitochondria in a presumably competitive manner. 23,27 As shown in Figure 6d and e, both interventions caused HK-II dissociation from isolated mitochondria and the effect of subsequent addition of recombinant kinase active Akt on Ca 2 þ -induced cytochrome c release was markedly diminished, supporting a critical role for mitochondrial HK-II in Akt-mediated protection. This conclusion was further supported by experiments demonstrating that Akt does not show protective effects when added to liver mitochondria (Figure 6f), which lack mitochondrial-associated HK-II.…”

Section: Resultsmentioning

confidence: 71%

“…[22][23][24][25][26] Interestingly the ability of Akt to protect against cytochrome c release and apoptosis in fibroblasts was shown to be decreased by HK-II dissociation from mitochondria. 27 The question of whether hexokinase is a mediator of cell survival in the heart has not been examined, although HK-II is abundantly expressed in cardiomyocytes. It is also not known whether PT-pore opening and mitochondrial integrity are regulated through the interaction of Akt and HK-II.…”

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confidence: 99%

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Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

2007

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Akt activation supports survival of cardiomyocytes against ischemia/reperfusion, which induces cell death through opening of the mitochondrial permeability transition pore (PT-pore). Mitochondrial depolarization induced by treatment of cardiomyocytes with H 2 0 2 is prevented by activation of Akt with leukemia inhibitory factor (LIF). This protective effect is observed even when cardiomyocytes treated with LIF are permeabilized and mitochondrial depolarization is elicited by elevating Ca 2 þ . Cell fractionation studies demonstrate that LIF treatment increases both total and phosphorylated Akt in the mitochondrial fraction. Furthermore, the association of Akt with HK-II is increased by LIF. HK-II contains consensus sequences for phosphorylation by Akt and LIF treatment induces PI3K-and Akt-dependent HK-II phosphorylation. Addition of recombinant kinase-active Akt to isolated adult mouse heart mitochondria stimulates phosphorylation of HK-II and concomitantly inhibits the ability of Ca 2 þ to induce cytochrome c release. This protection is prevented when HK-II is dissociated from mitochondria by incubation with glucose 6-phosphate or HK-II-dissociating peptide. Finally LIF increases HK-II association with mitochondria and dissociation of HK-II from mitochondria attenuates the protective effect of LIF on H 2 0 2 -induced mitochondrial depolarization in cardiomyocytes. We conclude that Akt has a direct effect at the level of the mitochondrion, which is mediated via phosphorylation of HK-II and results in protection of mitochondria against oxidant or Ca 2 þ -stimulated PT-pore opening.

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Section: Resultsmentioning

confidence: 71%

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confidence: 99%

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

2007

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“…Activated Akt is responsible for the translocation of hexokinase (dashed black arrow) from the cytoplasm to a site adjacent to the mitochondria, which is thought to enable increased flux through glycolysis. 37 Additionally, activated Akt inhibits the TSC1/TSC2, which in turn inhibits ras homolog enriched in brain leading to increased mTOR signaling. Increased mTOR activity enhances transcription of glycolytic enzymes, 38,39 protein synthesis through S6K and 4EBP1 phosphorylation, and cell growth.…”

Section: Ampk Activation In Cancer Cellsmentioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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“…Activated protein kinase B can suppress apoptosis. The activity of mitochondrial bound hexokinase was found to be important for protein kinase Blinked suppression of cytochrome c release and apoptosis [134].…”

Section: Hexokinase Inhibits Cytochrome C Releasementioning

confidence: 99%

The permeability transition pore in cell death

2007

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The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. The role of the PT-pore in apoptosisThe permeability transitionThe permeability transition (PT) is a sudden and sustained increase of the permeability of the inner mitochondrial membrane for solutes smaller than 1.5 kD. This has catastrophic consequences for this organelle. The mitochondrial membrane potential m , which relies on the im-permeability of the inner membrane for protons, breaks down and with it the ability of the cell to synthesize ATP. The ensuing blockade of the respiratory chain leads to the generation of reactive oxygen intermediates (ROIs), most likely via the direct transfer of electrons to molecular oxygen. Also, the high concentration of solutes in the mitochondrial matrix generates an osmotic pressure, which drives the influx of water molecules and the expansion of the extensively folded inner membrane and eventually disrupts the outer membrane leading to the release of factors that execute the suicide programme of apoptosis. Thus, the self-destruction of mitochondria via the PT is followed by the demise of the cell as a whole. This process of mitochondrial destruction was first observed in vitro but was dismissed at the time as an artefact because, among other reasons, it was inconceivable why mitochondria should dispose of a process to dismantle themselves. This changed, however, when it was shown that the PT is mediated by a protein complex, the so-called permeability transition pore (PT-pore), and that various physiological and pharmacological reagents can act on this pore and modify the deadly response of mitochondria. Finally, the realisation that cells can mount an active suicide response that is mediated in large part by mitochondria placed the PT-pore firmly on the map of researchers. In particular, the use of cyclosporine A (CsA) that can inhibit the PT-pore subunit cyc...

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Hexokinase-Mitochondria Interaction Mediated by Akt Is Required to Inhibit Apoptosis in the Presence or Absence of Bax and Bak

Cited by 582 publications

References 51 publications

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

AMP-activated protein kinase and human cancer: cancer metabolism revisited

The permeability transition pore in cell death

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