Kinnally K.W., Campo M.L., Tedeschi H. Mitochondrial channel activity studied by patch-clamping mitoplasts. The Ala14 residue of IF1 (Ser14 in human and mouse IF1) is highlighted in yellow. However, the activity of ATP synthase is counterbalanced by enhanced expression levels of IF1 that exert tumor suppressor activities in some carcinomas. 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]. In contrast, hypoxia and progression through the reductive phases of the cell cycle (S/G2/M) promote dephosphorylation of IF1, the reduction of OXPHOS and an enhanced glycolytic flux [76]. All authors have read and agreed to the published version of the manuscript. Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer. In addition, nebivolol also arrests proliferation of endothelial cells by blocking 1-adrenergic receptors impeding tumor angiogenesis [60]. Leanza L., Romio M., Becker K.A., Azzolini M., Trentin L., Manago A., Venturini E., Zaccagnino A., Mattarei A., Carraretto L., et al. Zhao Z., Mei Y., Wang Z., He W. The Effect of Oxidative Phosphorylation on Cancer Drug Resistance. Copyright Martinez-Reyes I., Diebold L.P., Kong H., Schieber M., Huang H., Hensley C.T., Mehta M.M., Wang T., Santos J.H., Woychik R., et al. In fact, at the beginning of this century, six hallmarks of the cancer phenotype were defined which included self-sufficiency in growth signals, insensitivity to anti-growth signals, limitless replicative potential, tissue invasion and metastasis, sustain angiogenesis and evading apoptosis [13]. Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-beta signaling. Wang D., Yin L., Wei J., Yang Z., Jiang G. ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. A working scheme summarizes the interplay of the two biomarkers of OXPHOS (-F1-ATPase and IF1) involved in the metastatic signature of lung adenocarcinomas [20]. Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Pedersen P.L. Gross A., Pilcher K., Blachly-Dyson E., Basso E., Jockel J., Bassik M.C., Korsmeyer S.J., Forte M. Biochemical and genetic analysis of the mitochondrial response of yeast to BAX and BCL-X(L). 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). In bladder carcinomas, hepatocarcinomas and gliomas, high expression levels of IF1 (red) predict a poor prognosis for the patients when compared to carcinomas with low levels of IF1 (blue). A Naturally Occurring Inhibitor of Mitochondrial Adenosine Triphosphatase. The Mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. The ATP synthase: The understood, the uncertain and the unknown. Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1alpha. Although the glycolytic phenotype is needed for tumor growth, metastatic disease requires the activity of OXPHOS, i.e., relatively high -F1-ATPase expression in the carcinoma. Wittig I., Schagger H. Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. An affinity purification approach of RNABPs using as bait the full-length -F1-ATPase mRNA allowed the identification of nine bona fide mRNA binding proteins [170]. In fact, the ATP synthase is structurally and functionally implicated in permeability transition (mPT) [96,97,98]. We need to talk about the Warburg effect. 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]. These results stress the relevance that translational control exerted by RNABPs has in the biogenesis of ATP synthase, and hence, in the bioenergetic signature and function of mitochondria. Jin L., Chun J., Pan C., Kumar A., Zhang G., Ha Y., Li D., Alesi G.N., Kang Y., Zhou L., et al. and J.M.C. Stem cells, iPSC and cancer cells have a predominant glycolytic phenotype whereas OXPHOS prevails in differentiated cells [180,181]. The spinning rotor then turns the internal stalk called -subunit, which passes through the center of the F1 subunits. We think that investigations aimed at characterizing the posttranscriptional mechanisms that regulate the activity of ATP synthase/IF1 axis will provide additional promising biomarkers for effective treatment of the disease. Inclusion in an NLM database does not imply endorsement of, or agreement with, Ricart J., Egea G., Izquierdo J.M., San Martin C., Cuezva J.M. WebInteractive animation of the structure of ATP. Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. The IF1 dimers (red) bind to two adjacent antiparallel ATP synthase dimers. As mentioned above, OXPHOS is required for metastatic disease (Figure 6) [20,129,130,131,133,147,179] and, consistently, melanoma, breast and lung carcinomas [20,66,144,146] with the highest expression level of -F1-ATPase predict higher chances of disease recurrence for the patients (Figure 6). Indeed, we showed that IF1 is phosphorylated in several serine residues in cells in cultures and in mouse hearts in vivo in response to cAMP-dependent activation of PKA [76]. Sleire L., Forde H.E., Netland I.A., Leiss L., Skeie B.S., Enger P.O. TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. 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]. Recent cryo-EM structures of mammalian tetrameric ATP synthases (Figure 4b) [90,91] and isobaric quantitative Protein Interaction Reporter (iqPIR) cross-linking technologies [84], have uncovered the structural role that IF1 plays in oligomerization and inhibition of ATP synthase, and in reprogramming of the tissue to an enhanced glycolysis [84]. Izquierdo J.M., Cuezva J.M. Simultaneously, the metabolism of glucose through the pentose phosphate pathway (PPP) is also significantly augmented, to produce the ribose that is used for building nucleotides and producing the NADPH that is used in biosynthetic processes and in the maintenance of the cellular redox state (Figure 1) [34]. Bethesda, MD 20894, Web Policies Warburg O. Fiorillo M., Ozsvari B., Sotgia F., Lisanti M.P. Similarly, the overexpression of IF1 in intestinal epithelial cells provides protection against inflammation (Figure 3) [81], whereas IF1 ablation results in a pro-inflammatory phenotype of fatal consequences [83]. Most available evidence suggests that regulation of IF1 expression is exerted at post-transcriptional levels by controlling the rates of its synthesis and degradation [182]. Moreover, the implication of the ATP synthase/IF1 axis in cell death, and as a promising target for cancer therapy, is also stressed. Lithgow T., Cuezva J.M., Silver P.A. On the origin of cancer cells. Torresano L., Nuevo-Tapioles C., Santacatterina F., Cuezva J.M. Garcia-Bermudez J., Sanchez-Arago M., Soldevilla B., Del Arco A., Nuevo-Tapioles C., Cuezva J.M. Molecular reconstruction from PDB: 6J5K. Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors. Scientists develop artificial metabolic pathway that uses electricity About ScienceDirect The enzymes that control metabolism are promising targets to combat progression of the disease [9,14,26,200,201]. Diethylnitrosamine-induced liver carcinogenesis in IF1-H49K transgenic mice contributed to an enhanced liver carcinogenesis by augmenting proliferation and apoptotic resistance of carcinoma cells [80]. Chen Q., Jiang H., Wang Z., Cai L.Y., Jiang Y.C., Xie L., Zhou Y., Zeng X., Ji N., Shen Y.Q., et al. Histidine-49 is necessary for the pH-dependent transition between active and inactive states of the bovine F1-ATPase inhibitor protein. Likewise, the overexpression of enzymes of metabolic pathways that are induced in carcinomas, such as glutamine metabolism [35,40,41] and the biosynthesis of fatty acids [35,42,43,44,45], predicts bad patient prognosis. Willers I.M., Isidoro A., Ortega A.D., Fernandez P.L., Cuezva J.M. Pt 2. Phosphoproteomic studies indicated that serine residues of IF1 are phosphorylated in cancer cells [185,186,187]. Contact and Sanchez-Arago M., Garcia-Bermudez J., Martinez-Reyes I., Santacatterina F., Cuezva J.M. The electrochemical energy stored in this gradient then drives the synthesis Interestingly, LRPPRC is tissue-specifically expressed [87] and the studies of its relevance in IF1-mRNA translation certainly deserves further investigations that will contribute to uncovering the tissue-specific mechanism that controls the activity of ATP synthase. Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis. WebInstead of using an ATP synthase as in respiration, ATP in fermentative organisms is The cellular signaling response mediated by IF1 overexpression is cell type specific in mouse tissues and promotes antioxidant responses, anti-inflammatory phenotypes and motor coordination and cognition. When IF1 is bound it is inhibited and no longer synthetizes nor hydrolyzes ATP. In this review, we summarize the role of the mitochondrial ATP synthase and the role of its inhibitor protein, the ATPase Inhibitory Factor 1 (IF1), in metabolic rewiring of cancer and its progression to emphasize the relevance that the engine that controls cellular life and death has in this field of investigation. The hallmarks of cancer. Overall, we believe that therapeutic approaches targeting the ATP synthase/IF1 axis and hence, the activity of OXPHOS in carcinomas, should take into consideration the tissue in which the carcinoma develops. Esparza-Molto P.B., Romero-Carraminana I., Nunez de Arenas C., Pereira M.P., Blanco N., Pardo B., Bates G.R., Sanchez-Castillo C., Artuch R., Murphy M.P., et al. Among them, G3BP1 (Ras-GTPase-Activating Protein SH3-Domain-Binding Protein) was found to interact both in vivo and in vitro with the 3UTR of -F1-ATPase mRNA, to promote inhibition of the synthesis of the protein by preventing mRNA translation [30,166,170]. Cruz-Bermudez A., Laza-Briviesca R., Vicente-Blanco R.J., Garcia-Grande A., Coronado M.J., Laine-Menendez S., Alfaro C., Sanchez J.C., Franco F., Calvo V., et al. Zhang Y., Chen F., Chandrashekar D.S., Varambally S., Creighton C.J. Furthermore, both in Acute Myeloid Leukemia and Chronic Myeloid Leukemia the downregulated expression of -F1-ATPase is exerted by hypermethylation of the promoter of the ATP5F1B gene, limiting the availability of -F1-ATPase mRNA in cancer cells [150,174]. Four ATP are produced during glycolysis, but two are consumed in the process, resulting in a net total of two ATP molecules. Selective inhibition of beta-F1-ATPase mRNA translation in human tumours. Metabolic pathways in cancer. Consistent with the reprogramming of metabolism in carcinomas, the sharp increase in different enzymes of glycolysis provide biomarkers that predict a bad patient prognosis [35], whereas, for example, the silencing of glycolytic enzymes in glioblastoma (GBM) xenografts dramatically increase the survival of mice [36]. Hence, it is possible to design therapies that simultaneously target two metabolic pathways of mitochondria. The Mitochondrial ATP Synthase/IF1 Axis in Cancer The work was supported by grants from MINECO (PID2019-108674RB-100), CIBERER-ISCIII (CB06/07/0017) and Fundacin Ramn Areces, Spain. Sanchez-Cenizo L., Formentini L., Aldea M., Ortega A.D., Garcia-Huerta P., Sanchez-Arago M., Cuezva J.M. The protective mechanisms. Remarkably, the signature included the two biomarkers of OXPHOS. Egea G., Izquierdo J.M., Ricart J., San Martn C., Cuezva J.M. Cabezon E., Butler P.J., Runswick M.J., Carbajo R.J., Walker J.E. Mootha V.K., Bunkenborg J., Olsen J.V., Hjerrild M., Wisniewski J.R., Stahl E., Bolouri M.S., Ray H.N., Sihag S., Kamal M., et al.

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