Lithium detaches hexokinase from mitochondria and inhibits proliferation of B16 melanoma cells

Penso, Julia; Beitner, Rivka

doi:10.1016/s1096-7192(02)00203-2

Cited by 26 publications

(25 citation statements)

References 22 publications

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“…This hypothesis is consistent with theoretical models predicting a higher probability of the Crabtree effect in the case of decreased permeability of the mitochondrial voltage-dependent anion channel and a high amount of hexokinase II attached to the outer mitochondrial membrane (30,31). Lithium chloride, which has an anti-proliferative effect on melanoma cells (32), induces detachment of hexokinase from mitochondria (33), and vice versa, the interaction of hexokinase II with voltage-dependent anion channel inhibits the release of cytochrome c from mitochondria induced by pro-apoptotic protein Bax (34). In this sense some synthetic polycation peptides are also able to inhibit the mitochondrial permeability transition (35).…”

supporting

confidence: 87%

Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

Lemeshko

Arias

Ordúz

2005

Journal of Biological Chemistry

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Bacillus thuringiensis subsp. medellin is known to produce the Cry11Bb protein of 94 kDa, which is toxic for mosquito larvae due to permeabilization of the plasma membrane of midgut epithelial cells. Earlier we found that a 2.8-kDa novel peptide BTM-P1, which was artificially synthesized taking into account the primary structure of Cry11Bb endotoxin, is active against several species of bacteria. In this work we show that BTM-P1 induces cyclosporin A-insensitive swelling of rat liver mitochondria in various salt solutions but not in the sucrose medium. Inorganic phosphate and Ca 2؉ significantly increased this effect of the peptide. The uncoupling action of BTM-P1 on oxidative phosphorylation was stronger in the potassiumcontaining media and correlated with a decrease of the inner membrane potential of mitochondria. In isotonic KNO 3 , KCl, or NH 4 NO 3 media, a complete drop of the inner membrane potential was observed at 1-2 g/ml of the peptide. The peptide-induced swelling was increased by energization of mitochondria in the potassium-containing media, but it was inhibited in the NaNO 3 , NH 4 NO 3 , and Tris-NO 3 media. All mitochondrial effects of the peptide were completely prevented by adding a single N-terminal tryptophan residue to the peptide sequence. We suggest a mechanism of membrane permeabilization that includes a transmembrane-and surface potential-dependent insertion of the polycation peptide into the lipid bilayer and its oligomerization leading to formation of ion channels and also to the mitochondrial permeability transition pore opening in a cyclosporin A-insensitive manner.

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supporting

confidence: 87%

Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

Lemeshko

Arias

Ordúz

2005

Journal of Biological Chemistry

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“…It has been stated that in conditions that glycolysis occurs at elevated rates, such as cancer, the particulate fraction of glycolytic enzyme, that is the fractions of these enzymes that are associated to intracellular ultrastructures, increases (17,41). Additionally, the detachment of these enzymes from intracellular ultrastructures has been proved to the lethal to tumor cells and is proposed as a target for anticancer drugs development (41,50,51,(54)(55)(56)(57). Similarly, promoting the association of glycolytic enzymes, these intracellular ultrastructures might be a possible mechanism for the prevention of complications associated to DM owing to the diminished glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva¹,

Ausina²,

Alencar³

et al. 2012

IUBMB Life

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SummaryDiabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects.

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“…In many cases, hexokinase detachment by itself is insufficient to cause cell death (Penso and Beitner, 2003;Majewski et al, 2004). Notably, jasmonates are distinct in their ability to cause considerable cell cytotoxicity by themselves.…”

Section: Discussionmentioning

confidence: 99%