Cabezon E., Butler P.J., Runswick M.J., Walker J.E. The supernumerary subunits include e (orange), f, g, A6L, the protein associated with diabetes in insulin-sensitive tissues (DAPIT), and the 6.8 kDa proteolipid (6.8PL) (light blue). Our studies in metabolic reprograming in human carcinomas revealed that normal lung, colon and breast tissues express negligible quantities of IF1 [85] but showed a sharp increase in the expression of the protein in the carcinomas and in cultured cancer cells [74,75,85]. Moreover, the implication of the ATP synthase/IF1 axis in cell death, and as a promising target for cancer therapy, is also stressed. However, while the upregulation of glycolysis in carcinomas is nowadays out of the question, the alteration of mitochondrial bioenergetics is still a matter of debate, despite the obvious evidence linking the down-regulation of mitochondrial metabolism and bioenergetics in cancer progression [20,35,51,115,116,117,118,119,120]. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. In this regard, antibiotics such as doxycycline that target the mitochondrial ribosome and inhibit translation prevent mitochondrial biogenesis which is required for the clonal expansion and survival of cancer stem cells (CSCs) [209]. K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. ATP Synthase and Chemiosmosis - Concept | Biology | JoVe Galluzzi L., Kepp O., Vander Heiden M.G., Kroemer G. Metabolic targets for cancer therapy. 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]. The Anti-Warburg Effect Elicited by the cAMP-PGC1alpha Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes. ATP Synthase - an overview | ScienceDirect Topics Human G3BP1 interacts with beta-F1-ATPase mRNA and inhibits its translation. Low OXPHOS cells (light orange cells; low of levels of -F1-ATPase and high levels of IF1) promote the growth of the primary tumor through an enforced glycolysis. WebATP synthase is a crucial enzyme that plays a vital role in energy production within cells. Interestingly, it should be noted that tissues that contain high expression levels of IF1 present both phospho- and dephosphorylated IF1 [76,87], consistent with the existence of two pools of ATP synthase in their mitochondria, active and IF1-bound inhibited enzyme [76]. 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]. Interestingly, we and others have demonstrated that the expression of IF1 prevents cell death [75,112,113] and promotes in vivo the oligomerization of ATP synthase in mouse livers, hearts, skeletal muscles and neurons [80,82,84,89], in agreement with cryo-EM studies that show that dimers of IF1 bind two antiparallel dimers of the ATP synthase in a tetrameric inhibited structure of the enzyme (Figure 4b) [90,91]. Doxycycline has also been used in combination with other anticancer therapies [210,211,212,213] and their effectiveness lies in their ability to prevent metastasis by inhibiting the growth of CSCs. In this scenario, the ATP synthase, that integrates the bioenergetic and death-signaling functions of mitochondria, is called to play a relevant function in cancer onset and progression. Esparza-Molto P.B., Nuevo-Tapioles C., Chamorro M., Najera L., Torresano L., Santacatterina F., Cuezva J.M. The biological rone and function on human atp synthase 500 words Hong X., Zhong L., Xie Y., Zheng K., Pang J., Li Y., Yang Y., Xu X., Mi P., Cao H., et al. Pedersen P.L. Besides the mechanisms that regulate the fraction of IF1 that is active as an inhibitor of the ATP synthase discussed above (Figure 2b), the mechanisms that control the overall mitochondrial content of IF1 are also of relevance. Barnes C.J., Li F., Mandal M., Yang Z., Sahin A.A., Kumar R. Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. In the heart, the inhibition an assembly deficit of ATP synthase is associated with the overexpression of IF1 [196]. Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization. Li K., Zhang C., Chen L., Wang P., Fang Y., Zhu J., Chen S., Du J., Shen B., Wu K., et al. 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. In fact, the ATP synthase is structurally and functionally implicated in permeability transition (mPT) [96,97,98]. Santacatterina F., Sanchez-Cenizo L., Formentini L., Mobasher M.A., Casas E., Rueda C.B., Martinez-Reyes I., Nunez de Arenas C., Garcia-Bermudez J., Zapata J.M., et al. However, the reprogramming of energy metabolism was not listed as a cancer hallmark at that stage. Cogliati S., Enriquez J.A., Scorrano L. Mitochondrial Cristae: Where Beauty Meets Functionality. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Reprogramming oxidative phosphorylation in cancer: A role for RNA binding proteins. MYC/PGC-1alpha Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization. Cancer metabolism: A therapeutic perspective. Extracellular electron transfer drives ATP synthesis for nitrogen 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]. WebThe mechanism, which depicts the reaction UTP + ATP + glutamine CTP + ADP + Deregulation of mitochondrial ATPsyn-beta in acute myeloid leukemia cells and with increased drug resistance. The renascence of Warburgs postulates in the cancer field was spurred by the implementation of Positron Emission Tomography (PET) in clinical oncology, using the radionuclide 18F-dexoxyglucose (18FDG) [16,17,18], which represents the bed-side translation of Warburgs metabolic observation regarding the glucose avidity of tumors [19]. Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. Received 2023 Jun 22; Revised 2023 Jul 18; Accepted 2023 Jul 21. Overall, these results suggest that OXPHOS is diminished, especially when compared to the sharp induction of glycolysis and other metabolic pathways (Figure 1). We have emphasized the mechanisms that control the expression and activity of -F1-ATPase and IF1 in cancer, which show similarities with those operating in development and differentiation, to highlight the relevance that post-transcriptional mechanisms play in the regulation of the mitochondrial phenotype of mammalian tissues and carcinomas. Et Biophys. 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]. 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). government site. The enzymes that control metabolism are promising targets to combat progression of the disease [9,14,26,200,201]. 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. Mitochondria and Cancer. Sheffer M., Bacolod M.D., Zuk O., Giardina S.F., Pincas H., Barany F., Paty P.B., Gerald W.L., Notterman D.A., Domany E. Association of survival and disease progression with chromosomal instability: A genomic exploration of colorectal cancer. Adenosine triphosphate - Wikipedia The generated mtROS modify the activity of protein kinases and of transcription factors that signal to the nucleus different programs that allow adaptation of the cell to changing cues (Figure 3) [75,79,80,81,82]. Chandel N.S. Scientists develop artificial metabolic pathway that uses electricity 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. Targeting Metabolism for Cancer Therapy. The ATP from the AAA cycle can be used to power chemical reactions, like The Ca2+-induced membrane transition in mitochondria. Specific increase in the translational efficiency of the nuclear-encoded mitochondrial beta-F1-ATPase mRNA. The active ATP synthase is able to synthetize ATP using ADP and Pi. Ricart J., Egea G., Izquierdo J.M., San Martin C., Cuezva J.M. ScienceDirect is a registered trademark of Elsevier B.V. Tumor mitochondria and the bioenergetics of cancer cells. Careers, Unable to load your collection due to an error. A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, without Retaining Antibiotic Activity. Hanahan D. Hallmarks of Cancer: New Dimensions. LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. When IF1 is bound it is inhibited and no longer synthetizes nor hydrolyzes ATP. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Perhaps the debate emerges due to the metabolic behavior of some cancer cells when growing in culture [121], differences in the mitochondrial proteome and activity in different tissues [122,123], the heterogeneity of the microenvironment of carcinomas [124,125,126,127,128] and/or the finding that metastatic disease requires an enhanced expression of OXPHOS proteins [129,130,131,132,133,134,135]. 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]. IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype. Moreover, the BEC index is essentially the same in lung, breast and esophageal carcinomas despite the large differences in the expression of these proteins in the corresponding non-tumor adjacent tissues (NAT) [141]. 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]. Highways for protein delivery to the mitochondria. Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study. 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). Metabolic reprogramming and metabolic dependency in T cells. In any case, mitochondrial structure and its proteomic composition is certainly altered in a large number of carcinomas [115,136,137,138,139] and, as recently reviewed [35], many of the mitochondrial proteins involved in OXPHOS and in other mitochondrial activities remain unaltered or inhibited when compared to their non-tumor adjacent tissues (NAT). Hence, nebivolol treatment promotes the arrest of colon, breast, lung and squamous cell carcinomas [20,60,225] by promoting a metabolic and redox crisis in cancer cells [60]. De Francesco E.M., Bonuccelli G., Maggiolini M., Sotgia F., Lisanti M.P. Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1alpha. 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]. Glycolysis, fermentation, pentose phosphate pathway (PPP), lipogenesis and glutaminolysis are enhanced (red circles) in carcinomas. cookies. 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. Arismendi-Morillo G. Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment. Cabezon E., Butler P.J., Runswick M.J., Carbajo R.J., Walker J.E. Li L., Liang Y., Kang L., Liu Y., Gao S., Chen S., Li Y., You W., Dong Q., Hong T., et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. Lithgow T., Cuezva J.M., Silver P.A. In addition, glucose is catabolized through the PPP to obtain NADPH (orange box), for biosynthetic processes and the maintenance of the cellular redox state, and ribose-5-P, for nucleic acid biosynthesis (green box). The total nitrogen production in the experimental group was 1.64 times that DErrico I., Salvatore L., Murzilli S., Lo Sasso G., Latorre D., Martelli N., Egorova A.V., Polishuck R., Madeyski-Bengtson K., Lelliott C., et al. WebPolyphenols have attracted attention in the fight against antibiotic-resistant bacteria, as Interestingly, and despite the content of -F1-ATPase is not increased in the whole cohort of LUAD studied [20], the analysis revealed that the subgroup of patients bearing carcinomas with the highest content of -F1-ATPase had a worse prognosis when compared to the low content subgroup of patients [20], in agreement with a previous report [66]. Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways. Lee M., Hirpara J.L., Eu J.Q., Sethi G., Wang L., Goh B.C., Wong A.L. DeBerardinis R.J., Chandel N.S. 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]. WebInstead of using an ATP synthase as in respiration, ATP in fermentative organisms is Mitochondrial complex III ROS regulate adipocyte differentiation. Ca(2+) binding to F-ATP synthase beta subunit triggers the mitochondrial permeability transition. Glutaminolysis feeds the TCA cycle with glutamate. Indeed, the overexpression of IF1 in forebrain neurons [82] and cardiomyocytes [84] or of the active mutant version of IF1 (H49K) in liver [80] and skeletal muscle [89] of transgenic mice promotes the oligomerization and inhibition of ATP synthase. 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. A mitochondrial megachannel resides in monomeric F1FO ATP synthase. Rigo P., Paulus P., Kaschten B.J., Hustinx R., Bury T., Jerusalem G., Benoit T., Foidart-Willems J. Oncological applications of positron emission tomography with fluorine-18 fluorodeoxyglucose. Answered: ATP synthase can break down ATP but it | bartleby support, Terms and Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. These findings raised the reasonable hypothesis that IF1 might represent a sort of mitochondrial oncogene [178], not only to control the hydrolytic activity of the ATP synthase, as it was postulated many years ago, but also its ATP synthetic activity. 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]. Books, Contact and For many years, it has been considered that under normal physiological situations, i.e., when the mitochondrial matrix pH is above neutrality, IF1 forms inactive oligomers by masking the inhibitory regions that bind to the F1 domain of the enzyme (Figure 2b) [175,176]. Interestingly, this mechanism of translational control for the expression of mitochondrial ATP synthase is operative in fetal human and rat livers but not in oncogenesis [173]. Samudio I., Harmancey R., Fiegl M., Kantarjian H., Konopleva M., Korchin B., Kaluarachchi K., Bornmann W., Duvvuri S., Taegtmeyer H., et al. Fiorillo C., Schena C.A., Quero G., Laterza V., Pugliese D., Privitera G., Rosa F., Schepis T., Salvatore L., Di Stefano B., et al. Hay N. Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy? Esparza-Molto P.B., Cuezva J.M. Reciprocal activation between ATPase inhibitory factor 1 and NF-kappaB drives hepatocellular carcinoma angiogenesis and metastasis. and transmitted securely. Finally, we summarize recent preclinical findings of the potential that OXPHOS and -oxidation have as targets to prevent cancer progression.
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