Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals

Zheng, Jianbiao; Ramírez, Victor D.

doi:10.1038/sj.bjp.0703397

Cited by 409 publications

(320 citation statements)

References 58 publications

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“…AMPK can also be activated by hormones and cytokines, including leptin, adiponectin, interleukin-6 and ciliary neurotrophic factor (CNTF) [7,45]. As a structural analogue of PMQ, quercetin was able to inhibit mitochondrial F0F1-ATPase activity and increase the AMP:ATP ratio, further activating AMPK [46]. Another study showed that quercetin activated AMPK by AMP-dependent and AMP-independent mechanisms [47].…”

Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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Aims/hypothesis Pentamethylquercetin (PMQ) has recently been shown to have glucose-lowering properties. Here, we aimed to characterise the effectiveness and underlying mechanisms of PMQ for ameliorating metabolic disorders in vivo and vitro. Methods We generated a mouse model of obesity by neonatal administration of monosodium glutamate (MSG) and used it to assess the properties of PMQ as a treatment for metabolic disorders. We also investigated the possible underlying mechanisms of PMQ in the prevention of metabolic disorders. Results Compared with normal mice, MSG mice had metabolic disorders, including central obesity, hyperinsulinaemia, insulin resistance, hyperglycaemia, hyperlipidaemia, decreased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated levels of GLUT4 in gastrocnemius muscles. In MSG mice, PMQ treatment (5, 10, 20 mg/kg daily) reduced body weight gain, waist circumference, adipose tissue mass, serum glucose, triacylglycerol and total cholesterol, while improving insulin resistance, activating AMPK and increasing ACC phosphorylation and GLUT4 abundance. In C2C12 myotubes, PMQ (10 μmol/l) increased glucose consumption by ∼65%. PMQ treatment (1-10 μmol/l) also activated AMPK, increased ACC phosphorylation and GLUT4 abundance, and upregulated the expression of some key genes involved in fatty acid oxidation. Conclusions/interpretation These findings suggest that PMQ can ameliorate metabolic disorders at least in part via stimulation of AMPK activity.

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Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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“…This is in contrast to angiostatin, which inhibited ATP production by greater than 70% in similar studies (see Table II). Piceatannol, a known inhibitor of mitochondrial F 1 -F 0 ATP synthase (22,23), inhibited ATP production by 75% at pH 6.1 and 92% at pH 7.7 (see Table I), which demonstrated that ATP synthase is the major source of ATP in this assay.…”

Section: If1mentioning

confidence: 95%

An Inhibitor of the F1 Subunit of ATP Synthase (IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface

Wahl

Fang

et al. 2005

Journal of Biological Chemistry

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Angiostatin binds to endothelial cell (EC) surface F 1 -F 0 ATP synthase, leading to inhibition of EC migration and proliferation during tumor angiogenesis. This has led to a search for angiostatin mimetics specific for this enzyme. A naturally occurring protein that binds to the F1 subunit of ATP synthase and blocks ATP hydrolysis in mitochondria is inhibitor of F1 (IF1). The present study explores the effect of IF1 on cell surface ATP synthase. IF1 protein bound to purified F 1 ATP synthase and inhibited F 1 -dependent ATP hydrolysis consistent with its reported activity in studies of mitochondria. Although exogenous IF1 did not inhibit ATP production on the surface of EC, it did conserve ATP on the cell surface, particularly at low extracellular pH. IF1 inhibited ATP hydrolysis but not ATP synthesis, in contrast to angiostatin, which inhibited both. In cell-based assays used to model angiogenesis in vitro, IF1 did not inhibit EC differentiation to form tubes and only slightly inhibited cell proliferation compared with angiostatin. From these data, we conclude that inhibition of ATP synthesis is necessary for an anti-angiogenic outcome in cell-based assays. We propose that IF1 is not an angiostatin mimetic, but it can serve a protective role for EC in the tumor microenvironment. This protection may be overridden in a concentration-dependent manner by angiostatin. In support of this hypothesis, we demonstrate that angiostatin blocks IF1 binding to ATP synthase and abolishes its ability to conserve ATP. These data suggest that there is a relationship between the binding sites of IF1 and angiostatin on ATP synthase and that IF1 could be employed to modulate angiogenesis.The term angiogenesis refers to the development of new blood vessels from preexisting vessels. This process is essential for maintaining and promoting tumor growth. One of the first anti-angiogenic agents discovered with the aim of treating cancers was angiostatin (1). Our laboratory identified F 1 -F 0 ATP synthase as a receptor for angiostatin on the surface of human EC 1 (2). This non-mitochondrial ATP synthase catalyzes ATP synthesis and is inhibited by angiostatin at low, tumor-like extracellular pH. The pH dependence explains the selectivity of angiostatin for the tumor microenvironment, where it inhibits EC migration and proliferation (3-5). Angiostatin inhibited both ATP production and ATP hydrolysis in previous studies (6). It was also demonstrated that polyclonal antibodies against the catalytic ␤-subunit or the regulatory ␣-subunit of ATP synthase inhibit the enzyme bidirectionally and therefore act as angiostatin mimetics. However, it was unknown whether a specific inhibitor of ATP hydrolysis could also serve as an angiostatin mimetic. To address this question, we have studied the effects of IF1, a natural inhibitor protein of F 1 -F 0 ATP synthase, on EC surface ATP synthase.The IF1 protein is a 9.6-kDa basic protein that comprises of 84 amino acids (7) and is known to inhibit the hydrolytic activity of mitochondrial ATP synthase (7,8...

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“…One of the many in vitro biochemical effects of resveratrol is to inhibit ATP hydrolysis and synthesis by the ATP synthase (F 1 F o -ATPase) found in mitochondria (11), as do the related natural products quercetin and piceatannol (12)(13)(14). Also, they inhibit ATP hydrolysis by its separate F 1 catalytic domain (15).…”

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confidence: 99%

Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols

Gledhill

Montgomery

Leslie

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

352

330

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The structures of F1-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4-and 2.7-Å resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three ␣-and three ␤-subunits beneath the ''crown'' of ␤-strands in their N-terminal domains. This region of F 1-ATPase forms a bearing to allow the rotation of the tip of the ␥-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the ␥-subunit and the ␤TP subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the ␥-subunit and either the ␤DP or the ␤E subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the ␥-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis. mitochondria ͉ oxidative phosphorylation ͉ rotary mechanism ͉ crystal structure

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Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals

Cited by 409 publications

References 58 publications

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

An Inhibitor of the F1 Subunit of ATP Synthase (IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface

Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols

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Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals

Cited by 409 publications

References 58 publications

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

An Inhibitor of the F1 Subunit of ATP Synthase (IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface

Mechanism of inhibition of bovine F 1 -ATPase by resveratrol and related polyphenols

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Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols