The inhibitor protein of the F1F0-ATP synthase is associated to the external surface of endothelial cells

Cortés-Hernández, Paulina; Domínguez-Ramírez, Lenin; Estrada-Bernal, Adriana; Montes-Sánchez, Delina G.; Zentella‐Dehesa, Alejandro; Gómez‐Puyou, Marietta Tuena de; Gómez‐Puyou, Armando; Garcia, J.

doi:10.1016/j.bbrc.2005.03.064

Cited by 28 publications

(17 citation statements)

References 26 publications

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“…This is in line with recent studies reporting ectopic localisation of endogenous IF1 at the cell surface of different cell types including endothelial cells [17] and hepatocytes [16], [18], [19]. Thus, IF1 is not strictly confined within the mitochondria but is ectopically expressed at the cell surface or circulating in human serum.…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, exogenous IF1 was able to reduce by about 50% HDL uptake by perfused rat liver [6], suggesting that the inhibitory effect of IF1 on ecto-F 1 -ATPase activity might impact on HDL metabolism. More recently, endogenous IF1 has been identified on the surface of both endothelial cells and hepatocytes [16], [17], [18], [19], suggesting that endogenous IF1 might also be a potent regulator of HDL metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Inhibitory Factor 1 (IF1) Is Present in Human Serum and Is Positively Correlated with HDL-Cholesterol

et al. 2011

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BackgroundMitochondrial ATP synthase is expressed as a plasma membrane receptor for apolipoprotein A-I (apoA-I), the major protein component in High Density Lipoproteins (HDL). On hepatocytes, apoA-I binds to cell surface ATP synthase (namely ecto-F1-ATPase) and stimulates its ATPase activity, generating extracellular ADP. This production of extracellular ADP activates a P2Y13-mediated HDL endocytosis pathway. Conversely, exogenous IF1, classically known as a natural mitochondrial specific inhibitor of F1-ATPase activity, inhibits ecto-F1-ATPase activity and decreases HDL endocytosis by both human hepatocytes and perfused rat liver.Methodology/Principal FindingsSince recent reports also described the presence of IF1 at the plasma membrane of different cell types, we investigated whether IF1 is present in the systemic circulation in humans. We first unambiguously detected IF1 in human serum by immunoprecipitation and mass spectrometry. We then set up a competitive ELISA assay in order to quantify its level in human serum. Analyses of IF1 levels in 100 normolipemic male subjects evidenced a normal distribution, with a median value of 0.49 µg/mL and a 95% confidence interval of 0.22–0.82 µg/mL. Correlations between IF1 levels and serum lipid levels demonstrated that serum IF1 levels are positively correlated with HDL-cholesterol and negatively with triglycerides (TG).Conclusions/SignificanceAltogether, these data support the view that, in humans, circulating IF1 might affect HDL levels by inhibiting hepatic HDL uptake and also impact TG metabolism.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Mitochondrial Inhibitory Factor 1 (IF1) Is Present in Human Serum and Is Positively Correlated with HDL-Cholesterol

et al. 2011

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“…Under this hypothesis, elevated IF1 might actually reflect increased functional activity of ecto-F 1 -ATPase as stimulated by apoA-I. This view is supported by recent studies reporting that endogenous IF1 is expressed at the plasma membrane of different cell lines, including hepatocytes, where it constitutively inhibits ecto-F 1 -ATPase activity [32–34]. One hypothesis is that apoA-I, which competes with IF1 for binding sites on ecto-F 1 -ATPase [12–15], contributes to the release of ecto-IF1 from ecto-F 1 -ATPase.…”

Section: Discussionmentioning

confidence: 71%

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Genoux

Lichtenstein

Ferrières

et al. 2016

BMC Med

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BackgroundEpidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C.MethodSerum IF1 levels were measured in 577 male participants with stable CAD (age 45–74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths.ResultsIF1 levels were positively correlated with HDL-C (rs = 0.40; P < 0.001) and negatively with triglycerides (rs = −0.21, P < 0.001) and CAD severity documented by the Gensini score (rs = −0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38–0.89 and 0.50 (0.28–0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02).ConclusionsWe investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0672-9) contains supplementary material, which is available to authorized users.

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“…Primarily known to negatively regulate ATP catalysis in the mitochondrion (25), it has recently been detected in the surface of epithelial cells (11) with a potential role in epithelial cell signaling involved in angiogenesis (5). Interestingly, an endothelial tyrosine kinase receptor similar to angiopoietin receptor 1 was also found to be increased in the microarray experiment, suggesting effects on the neurovascular system.…”

Section: Fluoxetine In Female Goldfishmentioning

confidence: 94%

Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus)

Mennigen

Martyniuk

Crump

et al. 2008

Physiological Genomics

128

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. Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus). Physiol Genomics 35: 273-282, 2008. First published September 2, 2008; doi:10.1152/physiolgenomics.90263.2008.-We investigated the effects of fluoxetine, a selective serotonin reuptake inhibitor, on neuroendocrine function and the reproductive axis in female goldfish. Fish were given intraperitoneal injections of fluoxetine twice a week for 14 days, resulting in five injections of 5 g fluoxetine/g body wt. We measured the monoamine neurotransmitters serotonin, dopamine, and norepinephrine in addition to their metabolites with HPLC. Homovanillic acid, a metabolite in the dopaminergic pathway, increased significantly in the hypothalamus. Plasma estradiol levels were measured by radioimmunoassay and were significantly reduced approximately threefold after fluoxetine treatment. We found that fluoxetine also significantly reduced the expression of estrogen receptor (ER)␤1 mRNA by 4-fold in both the hypothalamus and the telencephalon and ER␣ mRNA by 1.7-fold in the telencephalon. Fluoxetine had no effect on the expression of ER␤2 mRNA in the hypothalamus or telencephalon. Microarray analysis identified isotocin, a neuropeptide that stimulates reproductive behavior in fish, as a candidate gene affected by fluoxetine treatment. Real-time RT-PCR verified that isotocin mRNA was downregulated approximately sixfold in the hypothalamus and fivefold in the telencephalon. Intraperitoneal injection of isotocin (1 g/g) increased plasma estradiol, providing a potential link between changes in isotocin gene expression and decreased circulating estrogen in fluoxetine-injected fish. Our results reveal targets of serotonergic modulation in the neuroendocrine brain and indicate that fluoxetine has the potential to affect sex hormones and modulate genes involved in reproductive function and behavior in the brain of female goldfish. We discuss these findings in the context of endocrine disruption because fluoxetine has been detected in the environment. brain; estrogen receptors; isotocin; microarray; Prozac FLUOXETINE (PROZAC), a selective serotonin reuptake inhibitor (SSRI) (46), has been used in several studies in fish to investigate the serotonergic modulation of the endocrine system (55). A racemic mixture of two lipophilic enantiomers, fluoxetine is metabolized by cytochrome P-450 isoenzymes to the active metabolite norfluoxetine (46). In humans, fluoxetine is primarily excreted in urine as ϳ20%-30% unchanged parent compound, while metabolites are largely excreted as pharmacologically active norfluoxetine and inactive fluoxetine glucuronide (62).Fluoxetine also has effects on reproduction in several vertebrates. For example, in the goldfish (Carassius auratus), combined intraperitoneal administration of 10 g/g fluoxetine and 10 g/g serotonin (5-HT) elevated luteinizing hormone (LH) levels relative to 5-HT administration alone 2 h after treatment (55). Japanese medaka (Oryzias latipes) exposed to waterborne 0.1 and 0.5 g/l fluoxetine for 4 wk sh...

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The inhibitor protein of the F1F0-ATP synthase is associated to the external surface of endothelial cells

Cited by 28 publications

References 26 publications

Mitochondrial Inhibitory Factor 1 (IF1) Is Present in Human Serum and Is Positively Correlated with HDL-Cholesterol

Mitochondrial Inhibitory Factor 1 (IF1) Is Present in Human Serum and Is Positively Correlated with HDL-Cholesterol

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus)

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