In contrast, IF1 overexpression in skeletal muscle and heart is deleterious. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. use of Xing F., Luan Y., Cai J., Wu S., Mai J., Gu J., Zhang H., Li K., Lin Y., Xiao X., et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase. Hunter D.R., Haworth R.A. Zhang L., Dai L., Li D. Mitophagy in neurological disorders. Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis. Lithgow T., Cuezva J.M., Silver P.A. Internal-ribosome-entry-site functional activity of the 3-untranslated region of the mRNA for the beta subunit of mitochondrial H+-ATP synthase. It consists of two main domains, the Fo embedded in the IMM and the F1 domain projected into the matrix, containing the and subunits of the catalytic core (Figure 2b) [70]. The central stalk transfers this rotational energy to the 33 subunits in the F1 domain, leading to the synthesis of ATP (Figure 2b). A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. We highlight the cell-type specificity by which the ATP synthase/IF1 axis exerts its activity as a tumor promotor or signals an anti-metastatic phenotype. As reviewed elsewhere [73], the ATP5IF1 gene interacts with c-Myc, c-Fos, NFB and HIF-1 transcription factors. The Fo and F1 domains are linked together by a central (subunit , and ) and a peripheral (subunit b, d, OSCP and F6) stalk (Figure 2b). Cabezon E., Butler P.J., Runswick M.J., Carbajo R.J., Walker J.E. Accessibility On the contrary, nuclear reprogramming of somatic cells to induce pluripotency (iPSC) promotes the downregulation of OXPHOS concurrently with the activation of glycolysis [183] and the re-expression of high cellular levels of IF1 [184]. Lin P.C., Lin J.K., Yang S.H., Wang H.S., Li A.F., Chang S.C. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. However, the Warburg phenotype is reversible, and could be acquired with or without any oncogenic alteration as demonstrated by adaptation of cancer cells to changing environments [49,50,51,52,53,54,55,56,57,58]. In this regard, several glycolytic inhibitors have been proposed and some of them are actually in clinical trials [26,51,152,201,202,203,204]. Mol. -F1-ATPase mRNA localization and translation requires at least two cis-acting elements and a large set of RNABPs [156,158] and the 3-UTR of the mRNA that acts as a translational enhancer sequence [159,160,161,162]. In agreement with the pro-oncogenic role of IF1, studies in human hepatocellular carcinomas (HCC) showed that high levels of IF1 predict worse overall and progression free survival for the patients (Figure 5) [88]. Kahancova A., Sklenar F., Jezek P., Dlaskova A. Overexpression of native IF1 downregulates glucose-stimulated insulin secretion by pancreatic INS-1E cells. Hanahan D. Hallmarks of Cancer: New Dimensions. Drug repurposing in cancer. In contrast, the loss of mitochondrial proteins involved in pyruvate oxidation, -oxidation and OXPHOS predicts bad patient prognosis [35,37,38,39], supporting the theory that a diminished metabolic activity of the organelle compromises survival. The work was supported by grants from MINECO (PID2019-108674RB-100), CIBERER-ISCIII (CB06/07/0017) and Fundacin Ramn Areces, Spain. Mechanistically, nebivolol binds to 1-adrenergic receptors in cancer cells, causing the increase in IF1 content bound to the ATP synthase and promoting its inhibition. Remarkably, the results in tissues of mouse models with regulated expression of IF1 further suggest that mitochondria in non-stressed physiological conditions of some cellular types such as cardiomyocytes [76], neurons [82] and intestinal epithelial cells [83] contain a fraction of IF1-bound and -inhibited ATP synthase, in agreement with recent cryo-EM studies of mammalian heart ATP synthases [90,91]. More recently, the FDA-approved bedaquiline, which promotes the downregulation of the subunit of the ATP synthase, inhibits mitochondrial ATP production and metastasis in vivo [221,222]. Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. In fact, the IF1 protein has a very high turnover rate (23 h), both in cancer cells [85] and in differentiated osteocytes [182], which is much faster than the turnover of many other subunits of ATP synthase in cancer cells (18 h) [193]. Overall, despite that a high IF1 level confers to breast, colon and lung cancer cells a more glycolytic phenotype, it restrains tumor growth and metastatic disease by repressing OXPHOS and thus underpinning the better prognosis of the cancer patients that bear tumors with high expression levels of IF1 (Figure 5). In this regard, it should be noted that the activation of these cellular programs is different depending on the cell type as shown in tissue-specific mouse models of loss and gain of function of IF1 [79,80,81,84,89]. WebThe F-type proton ATPase is a multi-subunit enzyme of the F-type (also referred to as ATP Torresano L., Santacatterina F., Dominguez-Zorita S., Nuevo-Tapioles C., Nunez-Salgado A., Esparza-Molto P.B., Gonzalez-Llorente L., Romero-Carraminana I., Nunez de Arenas C., Sanchez-Garrido B., et al. Other examples are those afforded by metformin [218] and phenformin [219,220] that promote the inhibition of mitochondrial OXPHOS and reduce the risk of cancer in diabetic patients, increasing their rates of survival. Human normal tissues such as the heart, brain, kidney, stomach, endometrium and liver have a high IF1 content, whereas breast, colon, and lung epithelia contain negligible levels of IF1 [85,87]. 1Departamento de Biologa Molecular, Centro de Biologa Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientficas-Universidad Autnoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; se.cisc.mbc@zeugnimod.ainos, 2Centro de Investigacin Biomdica en Red de Enfermedades Raras (CIBERER) ISCIII, 28029 Madrid, Spain, 3Instituto de Investigacin Hospital 12 de Octubre, Universidad Autnoma de Madrid, 28041 Madrid, Spain. Viale A., Pettazzoni P., Lyssiotis C.A., Ying H., Sanchez N., Marchesini M., Carugo A., Green T., Seth S., Giuliani V., et al. Hu Y., Lu W., Chen G., Wang P., Chen Z., Zhou Y., Ogasawara M., Trachootham D., Feng L., Pelicano H., et al. The protective mechanisms. Gyawali B., Booth C.M. Furthermore, the BEC index significantly correlates with migration speed and in predicting drug responses across the NCI-60 cell line panel [151], as well as in predicting the response to different targeted therapies in preclinical mouse models bearing different human carcinomas [20,39,51,60,61,62,120,152,153]. A Review of the Inhibition of the Mitochondrial ATP Synthase by IF1 in vivo: Reprogramming Energy Metabolism and Inducing Mitohormesis. Prieto J., Seo A.Y., Leon M., Santacatterina F., Torresano L., Palomino-Schatzlein M., Gimenez K., Vallet-Sanchez A., Ponsoda X., Pineda-Lucena A., et al. Conversely, silencing or knocking out IF1 in cancer cells [20,179] and mouse models of loss of function of IF1 [82,83] resulted in and enhanced activity of the ATP synthase. The increase in m leads to an increase in the generation of mitochondrial reactive oxygen species (mtROS) at the electron transport chain that signal to the nucleus through kinases and transcription factors. In addition, IF1-mRNA is also subjected to tissue-specific translation control by RNABPs [30,195]. Sanchez-Arago M., Cuezva J.M. Specially, to prevent cancer recurrence and metastasis after conventional cancer therapies that render cancer cells OXPHOS-dependent [226,227,228,229]. https://creativecommons.org/licenses/by/4.0/. Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1alpha. De Francesco E.M., Bonuccelli G., Maggiolini M., Sotgia F., Lisanti M.P. Alavian K.N., Beutner G., Lazrove E., Sacchetti S., Park H.A., Licznerski P., Li H., Nabili P., Hockensmith K., Graham M., et al. Dobbelstein M., Moll U. Altogether, these findings emphasize the relevance of IF1 in metabolic reprogramming in cancer and pluripotent stem cells. Schulz T.J., Thierbach R., Voigt A., Drewes G., Mietzner B., Steinberg P., Pfeiffer A.F., Ristow M. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. Tri-phenyl-phosphonium (TPP)-related compounds also offer novel strategies for cancer treatment, as they inhibit CSC metastasis either as stand-alone [215] or in combination with an inhibitor of mitochondrial translation [216]. In fact, recent findings in isolated mitochondria of intestinal epithelial cells of IF1-ablated mice confirmed that IF1 is necessary to oligomerize and inhibit a fraction of ATP synthase [83]. Interestingly, LRPPRC specifically interacts with IF1-mRNA [30] and its over-expression in human and mouse cells significantly diminished the expression of IF1, increasing the rate of cellular ATP production [87]. WebProduction of ATP depends on the oxidation of energy-rich compounds to produce the Cogliati S., Enriquez J.A., Scorrano L. Mitochondrial Cristae: Where Beauty Meets Functionality. The Mitochondrial ATP Synthase/IF1 Axis in Cancer Targeting Metabolism for Cancer Therapy. Regulation of the ATP synthase is exerted by IF1. Remarkably, recent findings have demonstrated that the binding of kynurenic acid to the GPR35 orphan receptor prevents the phosphorylation of IF1 in human and mouse cardiomyocytes to prevent ATP hydrolysis as an anti-ischemic ATP-conservation mechanism [188,189]. Moreover, cyanine dyes also inhibit mitochondrial metabolism suppressing the growth CSCs impeding metastasis in vivo [217]. Mechanistically, the silencing of IF1 diminished the rates of proliferation, migration and invasive capacities of the cells, preventing epithelial mesenchymal transition (EMT) (Figure 5) [88,190,191]. However, it is remarkable that in the early phase of cell reprogramming of somatic cells into pluripotency, c-Myc is the transcription factor that triggers a sharp increase in IF1 expression, precipitating the metabolic program necessary for cellular reprogramming [184]. The accumulated evidence indicates that the metabolic reprogramming experienced in cancer provides new biomarkers that, alone or in combination, could be exploited to halt the disease in a successful personalized medicine. Reciprocal activation between ATPase inhibitory factor 1 and NF-kappaB drives hepatocellular carcinoma angiogenesis and metastasis. MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation. Post-transcriptional regulation of the mitochondrial H(+)-ATP synthase: A key regulator of the metabolic phenotype in cancer. Jin J., Byun J.K., Choi Y.K., Park K.G. In situations where the p collapses, such as hypoxia/anoxia, the ATP synthase acts in reverse to maintain the p at the expense of hydrolyzing ATP. Similar findings have been reported in large cohorts of breast [144] and melanoma [146] patients suggesting that, despite there being an overall limitation of OXPHOS in the carcinomas, mitochondrial bioenergetics is required for metastatic disease and cancer progression (see below) [131,154,155]. Boyer P.D. Likewise, the overexpression of IF1 in bladder carcinomas [190] and in gliomas [191] also predict a worse prognosis for the patients and a shorter time to disease recurrence (Figure 5). Esparza-Molto P.B., Cuezva J.M. Ortega A.D., Sanchez-Arago M., Giner-Sanchez D., Sanchez-Cenizo L., Willers I., Cuezva J.M. Hu S., Balakrishnan A., Bok R.A., Anderton B., Larson P.E., Nelson S.J., Kurhanewicz J., Vigneron D.B., Goga A. Ozsvari B., Sotgia F., Lisanti M.P. Acta. Proteomics technologies for cancer liquid biopsies. DeBerardinis R.J., Chandel N.S. Sleire L., Forde H.E., Netland I.A., Leiss L., Skeie B.S., Enger P.O. Specific increase in the translational efficiency of the nuclear-encoded mitochondrial beta-F1-ATPase mRNA. Hence, targeting mitochondrial ATP synthase and IF1 holds great promise for overcoming therapeutic resistance and impeding metastatic disease. Molecules | Free Full-Text | Cirsiliol and Quercetin Inhibit ATP Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance. Mild Ca2+ levels lead to closed and open states in a low-conductance mode of opening (flickering) in the PTP. Kahancova A., Sklenar F., Jezek P., Dlaskova A. mRNA encoding the beta-subunit of the mitochondrial F1-ATPase complex is a localized mRNA in rat hepatocytes. Overall, these results highlight mitochondria as a gold standard target for the effective treatment of a large diversity of carcinomas. Highways for protein delivery to the mitochondria. The majority of ATP synthase subunits are encoded in nuclear genes with the exception of two hydrophobic subunits (subunit a and 8 or A6L) that are encoded in the mitochondrial genome [70]. Ricart J., Egea G., Izquierdo J.M., San Martin C., Cuezva J.M. Mitochondria are central hubs in cellular physiology integrating cellular metabolism, bioenergetics, the execution of cell death and signaling through different effectors like Ca2+, reactive oxygen species (mtROS), mtDNA and different metabolites [1,2,3,4]. The electrochemical energy stored in this gradient then drives the synthesis Energy metabolism provides a therapeutic target with great potential for the treatment of cancer patients, since it is a trait of the disease that is reversible and amenable to modifications by inhibitors of the enzymes that steer metabolism [20,60,61,62,63,64,65,66]. Subcellular structure containing mRNA for beta subunit of mitochondrial H+-ATP synthase in rat hepatocytes is translationally active. Pullman M.E., Monroy G.C. Giorgio V., von Stockum S., Antoniel M., Fabbro A., Fogolari F., Forte M., Glick G.D., Petronilli V., Zoratti M., Szabo I., et al. Interestingly, the IF1-H49K mutant retains its inhibitory activity on the enzyme even at pHs above 6.7, both in vitro [74,85,175,177] and in vivo under basal physiological conditions of mitochondria [79,80,89]. The ATP synthase utilizes p by coupling the backflow of protons into the matrix of the organelle for the generation of ATP from ADP and inorganic phosphate (Pi) (Figure 2a). Sanchez-Arago M., Formentini L., Martinez-Reyes I., Garcia-Bermudez J., Santacatterina F., Sanchez-Cenizo L., Willers I.M., Aldea M., Najera L., Juarranz A., et al. In fact, the increase in protein content of IF1 in carcinomas [85] or its sharp reduction during cellular differentiation [182], are exerted in the absence of relevant changes in the abundance of IF1-mRNA. Lee M., Hirpara J.L., Eu J.Q., Sethi G., Wang L., Goh B.C., Wong A.L. Remarkably, five out of the six proteins in the signature are mitochondrial proteins, strongly suggesting that the mitochondrial proteome is a most relevant target in metabolic reprogramming of LUAD [20]. In these carcinomas, IF1 acts as a tissue-specific tumor promotor facilitating proliferation, angiogenesis, epithelial mesenchymal transition (EMT) and metastasis. WebThe thylakoid ATP synthase is a CF1FO-ATP synthase similar to the mitochondrial ATPase. The expression of the catalytic subunit of ATP synthase (-F1-ATPase) in mammalian liver is complex, including the subcellular localization of its mRNA in a structure that is frequently found attached to the outer mitochondrial membrane [156,157]. Sanchez-Arago M., Garcia-Bermudez J., Martinez-Reyes I., Santacatterina F., Cuezva J.M. In some mouse tissues, the IF1-mediated activation of mtROS signaling promotes long-lasting metabolic and molecular cytoprotective mechanisms that allow cells to withstand subsequent insults (Figure 3) [79,80,81], a process known as mitohormesis [1,2,3,86]. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Thylakoid - Wikipedia Yizhak K., Le Devedec S.E., Rogkoti V.M., Baenke F., de Boer V.C., Frezza C., Schulze A., van de Water B., Ruppin E. A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration. Histidine-49 is necessary for the pH-dependent transition between active and inactive states of the bovine F1-ATPase inhibitor protein. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. The regulation of IF1 activity as an inhibitor of ATP synthase is also exerted by covalent modification of the protein by phosphorylation (Figure 2b). However, the mitochondrial oxidation of pyruvate, -oxidation (-Ox. A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, without Retaining Antibiotic Activity. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Veiga S.R., Ge X., Mercer C.A., Hernandez-Alvarez M.I., Thomas H.E., Hernandez-Losa J., Ramon Y.C.S., Zorzano A., Thomas G., Kozma S.C. Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR. Mascaraque-Checa M., Gallego-Rentero M., Nicolas-Morala J., Portillo-Esnaola M., Cuezva J.M., Gonzalez S., Gilaberte Y., Juarranz A. Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy. Bonnet S., Archer S.L., Allalunis-Turner J., Haromy A., Beaulieu C., Thompson R., Lee C.T., Lopaschuk G.D., Puttagunta L., Bonnet S., et al. Camarda R., Zhou A.Y., Kohnz R.A., Balakrishnan S., Mahieu C., Anderton B., Eyob H., Kajimura S., Tward A., Krings G., et al. PTP opening leads to mitochondrial swelling and cell death and is regulated by Ca2+ and/or cyclophilin D-dependent structural changes on ATP synthase [97,102], whereas it is inhibited by cyclosporine A (CsA) [103,104]. WebPolyphenols have attracted attention in the fight against antibiotic-resistant bacteria, as Moreover, we have highlighted how the ATP synthase/IF1 axis contributes to the signaling of cell-type specific programs that allow the adaptation of the cell/organisms to different changing cues, and finally, how the ATP synthase/IF1 axis also participates in preventing the execution of cell death and hence, in therapeutic resistance of the carcinomas. Vazquez F., Lim J.H., Chim H., Bhalla K., Girnun G., Pierce K., Clish C.B., Granter S.R., Widlund H.R., Spiegelman B.M., et al. The cancer imaging technique stimulated metabolically oriented omic investigations of human carcinomas that opened up new windows of hope in cancer patients for its potential in diagnostic, staging, treatment and follow up of the disease [20,21,22,23,24,25]. Faccenda D., Tan C.H., Seraphim A., Duchen M.R., Campanella M. IF1 limits the apoptotic-signalling cascade by preventing mitochondrial remodelling. Pyruvate is reduced to lactate in fermentation to regenerate NAD+ to allow glycolysis to proceed and is exported from the cell. Gatenby R.A., Gillies R.J. Why do cancers have high aerobic glycolysis? Glycolysis and fermentation do not require oxygen to function. Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. The Ca2+-induced membrane transition in mitochondria. Garcia-Aguilar A., Cuezva J.M. Despite major genetic advances in the understanding of cancer, cancer patients still require the development of innovative therapeutic strategies matched to the phenotype of their tumors to halt progression of the disease. Molecular reconstruction from PDB: 7AJD; (b) Cryo-electron microscopy structure of porcine IF1-inhibited ATP synthase tetramers viewed from the matrix side. Actually, and depending on the type of carcinoma, the expression levels of IF1 define its activity as a tumor suppressor or as an oncogene. As previously mentioned, and besides controlling energy metabolism, the fraction of IF1-bound inhibited ATP synthase in the carcinomas is also fulfilling additional functions through signaling a pro-oncogenic phenotype, by stimulating proliferation/invasion/metastasis (Figure 5) [75,80,88,190,191], or an anti-oncogenic phenotype, by preventing metastatic disease and immune surveillance (Figure 5) (see next section) [20,85,147,179,192]. Min L., Ruan Y., Shen Z., Jia D., Wang X., Zhao J., Sun Y., Gu J. Overexpression of Ras-GTPase-activating protein SH3 domain-binding protein 1 correlates with poor prognosis in gastric cancer patients. Arismendi-Morillo G. Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment. Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F1 subcomplex. WebFigure 4.15 (a) The electron transport chain is a set of molecules that supports a series of The roles of protein synthesis and of adenine nucleotides. Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization. Fatty acids (FA) oxidation also feeds acetyl-CoA to the TCA cycle. Indeed, we have targeted lung adenocarcinomas in mice by restraining the assimilation of fatty acids with orlistat, or its oxidation in mitochondria with etomoxir, in both cases in combination with nebivolol [20]. Site-specific phosphodeficient and phosphomimetic IF1 serine mutants revealed that the PKA-mediated phosphorylation of IF1 in S39, but not in other serine residues, prevented the interaction of IF1 with ATP synthase and enhanced both the ATP synthetic and hydrolytic activities of the enzyme (Figure 2b) [76]. government site. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Whereas oncogenesis in epithelial cells of the endometrium, stomach and kidney does not promote an increase in IF1 expression, carcinomas in the colon, lung and breast show a very sharp increase in the content of IF1 [85]. Wang R., Green D.R. It was a decade later that a review by the same authors included two additional hallmarks of cancer: the avoidance of immune surveillance and the reprogramming of metabolism [14,15]. A mitochondrial megachannel resides in monomeric F1FO ATP synthase. The active ATP synthase is able to synthetize ATP using ADP and Pi. Labuschagne C.F., Cheung E.C., Blagih J., Domart M.C., Vousden K.H. Homologous and heterologous inhibitory effects of ATPase inhibitor proteins on F-ATPases. Moreover, metastatic breast cancer cells have lower IF1 levels when compared to the primary tumors [199], suggesting that metastatic cells rely on OXPHOS when compared to cancer cells in the primary tumor (Figure 6) [131]. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) is a metabolic regulator of intestinal epithelial cell fate. In addition, there are mobile electron carriers such as coenzyme Q (CoQ) and cytochrome c (cyt c), as well as membrane transporters that include among others the pyruvate carrier (not shown), adenine nucleotide translocase (ANT) and the phosphate carrier (PiC). Mitochondrial ROS Signaling in Organismal Homeostasis. In fact, we showed that IF1 overexpressing cancer cells proliferate, migrate and invade less than cancer cells with low expression levels or that are devoid of IF1 (Figure 5) [20,147,179]. Respiratory complexes of the ETC, and a variety of FAD-dependent dehydrogenases that feed electrons directly to CoQ, transfer electrons obtained in biological oxidations in the form of NADH and FADH2 down to molecular oxygen, to generate the proton electrochemical gradient responsible for the proton-motive force (p) across the IMM (Figure 2a). Shi Y., Lim S.K., Liang Q., Iyer S.V., Wang H.Y., Wang Z., Xie X., Sun D., Chen Y.J., Tabar V., et al. The role of ATP synthase/IF1 axis in metabolic reprogramming and signaling. mPT is exerted through a high-conductance channel in the IMM, known as the Permeability Transition Pore (PTP) [99,100,101]. Xiao X., Yang J., Li R., Liu S., Xu Y., Zheng W., Yi Y., Luo Y., Gong F., Peng H., et al. Dey R., Moraes C.T. These findings suggest that transformations blur the tissue-specific differences in energy metabolism to converge on the same metabolic phenotype that sustains tumor growth. Pinke G., Zhou L., Sazanov L.A. Cryo-EM structure of the entire mammalian F-type ATP synthase. In the last decade, we and others have demonstrated that IF1 not only inhibits the ATPase activity of the enzyme, but also inhibits its ATP synthetic activity [74,75,76,77,78], promoting the re-emergence of IF1 as the natural physiological inhibitor of both ATP synthase activities, mostly by results in genetic mouse models of loss and gain of function of Atp5if1 [79,80,81,82,83,84]. (13)C-Pyruvate Imaging Reveals Alterations in Glycolysis that Precede c-Myc-Induced Tumor Formation and Regression. Indeed, the phosphorylation of IF1 has been observed when there is an increase in energy demand in the heart in vivo or in cells in cultures when they are forced to increase OXPHOS [76]. Contrariwise, the silencing of LRPPRC in human and mouse cells augmented IF1 expression and reduced the ATP synthesis rate of the cells [87]. The Ala14 residue of IF1 (Ser14 in human and mouse IF1) is highlighted in yellow. Garcia-Ledo L., Nuevo-Tapioles C., Cuevas-Martin C., Martinez-Reyes I., Soldevilla B., Gonzalez-Llorente L., Cuezva J.M. In fact, the ATP synthase is structurally and functionally implicated in permeability transition (mPT) [96,97,98]. Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer. Glycolysis, fermentation, pentose phosphate pathway (PPP), lipogenesis and glutaminolysis are enhanced (red circles) in carcinomas. MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. We propose that nebivolol is a very strong candidate to be repurposed in basket trials, those in which cancer patients with carcinomas from different origins are included. Folmes C.D., Nelson T.J., Martinez-Fernandez A., Arrell D.K., Lindor J.Z., Dzeja P.P., Ikeda Y., Perez-Terzic C., Terzic A. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Webenoids, and drive photosynthetic electron transport able ATP production by the ATP In the monomer/monomer interfaces model, the Ca2+ induced conformational changes in dimers of the ATP synthase destabilize the dimeric assembly opening a high conductance pore in the interface of the dimer (subunits e and g).
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