Skip to main content

Advertisement

SpringerLink
Log in

F1Fo adenosine triphosphate (ATP) synthase is a potential drug target in non-communicable diseases

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

F1Fo adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. F1Fo ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. F1Fo ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the F1Fo ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of F1Fo ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

NCDs:

Non-communicable diseases

COP:

Chronic obstructive pulmonary

ATP:

Adenosine triphosphate

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid

ETC:

Electron transport chain

OXPHOS:

Oxidative phosphorylation

mPTP:

Mitochondrial permeability transition pore

ERRs:

Estrogen-related receptors

USF2:

Upstream stimulatory factor 2

CHF:

Congestive heart failure

IF1:

Inhibitory factor 1

hsTnT:

Troponin T

CAD:

Coronary artery disease

Mfn2:

Mitofusin-2

AD:

Alzheimer’s disease

CNS:

Central nervous system

CsA:

Cyclosporin A

ALS:

Amyotrophic lateral sclerosis

8-Cl-Ado:

8-Chloroadenosine

Bz-423:

Benzodiazepine

MDCK:

Mammalian renal epithelial cells

EGCG:

Epigallocatechin gallate

T1AM:

3-Iodothyronamine

References

  1. World Health Organization [WHO] (2016) Noncommunicable diseases country profiles 2018 Nepal

  2. Allen L (2016) Noncommunicable disease research. Int J Noncommunicable Dis 1:131. https://doi.org/10.4103/2468-8827.198586

    Article  Google Scholar 

  3. Snezhkina AV, Kudryavtseva AV, Kardymon OL et al (2020) ROS generation and antioxidant defense systems in normal and malignant cells. Oxid Med Cell Longev 2019:1–17. https://doi.org/10.1155/2019/6175804

    Article  CAS  Google Scholar 

  4. Casey JR, Grinstein S, Orlowski J (2010) Sensors and regulators of intracellular pH. Nat Rev Mol Cell Biol 11:50–61

    Article  CAS  PubMed  Google Scholar 

  5. Staples JF, Buck LT (2009) Matching cellular metabolic supply and demand in energy-stressed animals. Comp Biochem Physiol - A Mol Integr Physiol 153:95–105

    Article  PubMed  Google Scholar 

  6. Sokolova I (2018) Mitochondrial adaptations to variable environments and their role in animals’ stress tolerance. Integr Comp Biol 58:519–531. https://doi.org/10.1093/icb/icy017

    Article  CAS  PubMed  Google Scholar 

  7. Ye J (2021) Mechanism of insulin resistance in obesity: a role of ATP. Front Med 15:372–382

    Article  PubMed  Google Scholar 

  8. Hasanpourghadi M, Majid NA, Mustafa MR (2018) The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells. Peer J. https://doi.org/10.7717/peerj.5577

    Article  PubMed  PubMed Central  Google Scholar 

  9. Schmid AI, Szendroedi J, Chmelik M et al (2011) Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care 34:448–453. https://doi.org/10.2337/dc10-1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rouslin W, Erickson JL, Solaro RJ (1986) Effects of oligomycin and acidosis on rates of ATP depletion in ischemic heart muscle. Am J Physiol Hear Circ Physiol. https://doi.org/10.1152/ajpheart.1986.250.3.h503

    Article  Google Scholar 

  11. Zhao G, Joca HC, Nelson MT, Lederer WJ (2020) ATP- and voltage-dependent electro-metabolic signaling regulates blood flow in heart. Proc Natl Acad Sci USA 117:7461–7470. https://doi.org/10.1073/pnas.1922095117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tinker A, Aziz Q, Li Y, Specterman M (2018) ATP-sensitive potassium channels and their physiological and pathophysiological roles. Compr Physiol 1:1

    Google Scholar 

  13. Abrahams JP, Leslie AGW, Lutter R, Walker JE (1994) Structure at 2.8 Â resolution of F1-ATPase from bovine heart mitochondria. Nature 370:621

    Article  CAS  PubMed  Google Scholar 

  14. Chi SL, Pizzo SV (2006) Cell surface F1Fo ATP synthase: a new paradigm? Ann Med 38:429–438. https://doi.org/10.1080/07853890600928698

    Article  CAS  PubMed  Google Scholar 

  15. Das B, Mondragon MOH, Sadeghian M et al (1994) A novel ligand in lymphocyte-mediated cytotoxicity: expression of the β subunit of H + transporting ATP synthase on the surface of tumor cell lines. J Exp Med 180:273

    Article  CAS  PubMed  Google Scholar 

  16. Miranda-Astudillo H, Ostolga-Chavarría M, Cardol P, González-Halphen D (2022) Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae. Biochim Biophys Acta Bioenerg 1863:148569. https://doi.org/10.1016/j.bbabio.2022.148569

    Article  CAS  PubMed  Google Scholar 

  17. Wollweber F, von der Malsburg K, van der Laan M (2017) Mitochondrial contact site and cristae organizing system: a central player in membrane shaping and crosstalk. Biochim Biophys Acta Mol Cell Res 1864:1481–1489. https://doi.org/10.1016/j.bbamcr.2017.05.004

    Article  CAS  PubMed  Google Scholar 

  18. Juhaszova M, Kobrinsky E, Zorov DB et al (2022) ATP synthase K+- and H+-Fluxes drive ATP synthesis and enable mitochondrial K+-“Uniporter” function: I characterization of Ion Fluxes. Function. https://doi.org/10.1093/function/zqab065

    Article  PubMed  PubMed Central  Google Scholar 

  19. Morciano G, Naumova N, Koprowski P et al (2021) The mitochondrial permeability transition pore: an evolving concept critical for cell life and death. Biol Rev 96:2489–2521. https://doi.org/10.1111/brv.12764

    Article  CAS  PubMed  Google Scholar 

  20. Bonora M, Morganti C, Morciano G et al (2017) Mitochondrial permeability transition involves dissociation of F 1 F O ATP synthase dimers and C-ring conformation. EMBO Rep 18:1077–1089. https://doi.org/10.15252/embr.201643602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anand U (2011) The Beauty and Truth of the citric acid cycle. Clin Chem 57:1623–1624. https://doi.org/10.1373/clinchem.2011.166785

    Article  CAS  Google Scholar 

  22. Song R, Song H, Liang Y et al (2014) Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology 60:1659–1673. https://doi.org/10.1002/hep.27312

    Article  CAS  PubMed  Google Scholar 

  23. Morais AL, Rijo P, Batanero Hernán MB, Nicolai M (2020) Biomolecules and Electrochemical Tools in Chronic Non-Communicable Disease Surveillance: a systematic review. Biosensors 10:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Von Ballmoos C, Wiedenmann A, Dimroth P (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annu Rev Biochem 78:649–672. https://doi.org/10.1146/annurev.biochem.78.081307.104803

    Article  CAS  Google Scholar 

  25. Gallinat A, Badimon L (2022) DJ-1 interacts with the ectopic ATP-synthase in endothelial cells during acute ischemia and reperfusion. Sci Rep 12:1–12. https://doi.org/10.1038/s41598-022-16998-3

    Article  CAS  Google Scholar 

  26. Manson MD, Tedesco P, Berg HC et al (1977) A protonmotive force drives bacterial flagella. Proc Natl Acad Sci USA 74:3060–3064. https://doi.org/10.1073/pnas.74.7.3060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cox GB, Fimmel AL, Gibson F, Hatch L (1986) The mechanism of ATP synthase: a reassessment of the functions of the b and a subunits. BBA Bioenerg 849:62–69. https://doi.org/10.1016/0005-2728(86)90096-4

    Article  CAS  Google Scholar 

  28. Zhou A, Rohou A, Schep DG et al (2015) Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM. Elife. https://doi.org/10.7554/eLife.10180

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bernardi P, Di Lisa F, Fogolari F, Lippe G (2015) From ATP to PTP and back: a dual function for the mitochondrial ATP synthase. Circ Res 116:1850–1862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pérez MJ, Quintanilla RA (2017) Development or disease: duality of the mitochondrial permeability transition pore. Dev Biol 426:1–7. https://doi.org/10.1016/j.ydbio.2017.04.018

    Article  CAS  PubMed  Google Scholar 

  31. Quintana-Cabrera R, Quirin C, Glytsou C et al (2018) The cristae modulator optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nat Commun. https://doi.org/10.1038/s41467-018-05655-x

    Article  PubMed  PubMed Central  Google Scholar 

  32. Williams GSB, Boyman L, Lederer WJ (2015) Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 78:35–45

    Article  CAS  PubMed  Google Scholar 

  33. Nesci S, Trombetti F, Ventrella V, Pagliarani A (2018) From the Ca2+-activated F1FO-ATPase to the mitochondrial permeability transition pore: an overview. Biochimie 152:85–93

    Article  CAS  PubMed  Google Scholar 

  34. Bernardi P, Forte M (2008) The mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. J Biol Chem 283:26307–26311

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mnatsakanyan N, Jonas EA (2020) ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration. J Mol Cell Cardiol 144:109–118. https://doi.org/10.1016/j.yjmcc.2020.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wagner K, Rehling P, Sanjuán Szklarz LK et al (2009) Mitochondrial F1Fo-ATP synthase: the small subunits e and g associate with monomeric complexes to trigger dimerization. J Mol Biol 392:855–861. https://doi.org/10.1016/j.jmb.2009.07.059

    Article  CAS  PubMed  Google Scholar 

  37. Davies KM, Anselmi C, Wittig I et al (2012) Structure of the yeast F 1F o-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc Natl Acad Sci USA 109:13602–13607. https://doi.org/10.1073/pnas.1204593109

    Article  PubMed  PubMed Central  Google Scholar 

  38. Paumard P (2002) The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 21:221–230. https://doi.org/10.1093/emboj/21.3.221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Desvergne B, Michalik L, Wahli W (2006) Transcriptional regulation of metabolism. Physiol Rev 86:465–514

    Article  CAS  PubMed  Google Scholar 

  40. Yasuo K, Shigeo O (1990) Regulation of mitochondrial ATP synthesis in mammalian cells by transcriptional control. Int J Biochem 22:219–229. https://doi.org/10.1016/0020-711X(90)90333-X

    Article  Google Scholar 

  41. Houštek J, Klement P, Floryk D et al (1999) A novel deficiency of mitochondrial ATPase of nuclear origin. Hum Mol Genet 8:1967–1974. https://doi.org/10.1093/hmg/8.11.1967

    Article  PubMed  Google Scholar 

  42. Houštěk J, Kmoch S, Zeman J (2009) TMEM70 protein—A novel ancillary factor of mammalian ATP synthase. Biochim Biophys Acta Bioenerg 1787:529–532. https://doi.org/10.1016/j.bbabio.2008.11.013

    Article  CAS  Google Scholar 

  43. Houštěk J, Pícková A, Vojtíšková A et al (2006) Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta Bioenerg 1757:1400–1405. https://doi.org/10.1016/j.bbabio.2006.04.006

    Article  CAS  Google Scholar 

  44. Ding D, Enriquez-Algeciras M, Dave KR et al (2012) The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis. EMBO Rep 13:230–236. https://doi.org/10.1038/embor.2011.264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang Q, Li Y (2007) Roles of PPARs on regulating myocardial energy and lipid homeostasis. J Mol Med 85:697–706

    Article  CAS  PubMed  Google Scholar 

  46. Gronda E, Lovett EG, Tarascio M et al (2014) The baroreceptor as a therapeutic target for heart failure. J Cardiovasc Transl Res 7:301–309. https://doi.org/10.1007/s12265-014-9546-8

    Article  PubMed  Google Scholar 

  47. Vander Zee CA, Jordan EM, Breen GAM (1994) ATPF1 binding site, a positive cis-acting regulatory element of the mammalian ATP synthase α-subunit gene. J Biol Chem 269:6972

    Article  CAS  PubMed  Google Scholar 

  48. Breen GAM, Jordan EM (1998) Upstream stimulatory factor 2 activates the mammalian F1F0 ATP synthase α-subunit gene through an initiator element. Gene Expr 7:163–170

    CAS  PubMed  Google Scholar 

  49. Willers IM, Isidoro A, Ortega ÁD et al (2010) Selective inhibition of β-F1-ATPase mRNA translation in human tumours. Biochem J 426:319–326. https://doi.org/10.1042/BJ20091570

    Article  CAS  PubMed  Google Scholar 

  50. Sangawa H, Himeda T, Shibata H, Higuti T (1997) Gene expression of subunit c(P1), subunit c(P2), and oligomycin sensitivity-conferring protein may play a key role in biogenesis of H+-ATP synthase in various rat tissues. J Biol Chem 272:6034–6037. https://doi.org/10.1074/jbc.272.9.6034

    Article  CAS  PubMed  Google Scholar 

  51. Rak M, Tzagoloff A (2009) F1-dependent translation of mitochondrially encoded Atp6p and Atp8p subunits of yeast ATP synthase. Proc Natl Acad Sci USA 106:18509–18514. https://doi.org/10.1073/pnas.0910351106

    Article  PubMed  PubMed Central  Google Scholar 

  52. Harris DA, Das AM (1991) Control of mitochondrial ATP synthesis in the heart. Biochem J 280:561–573. https://doi.org/10.1042/bj2800561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ashrafian H, Redwood C, Blair E, Watkins H (2003) Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet 19:263–268. https://doi.org/10.1016/S0168-9525(03)00081-7

    Article  CAS  PubMed  Google Scholar 

  54. Marín-García J, Goldenthal MJ, Moe GW (2001) Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc Res 52:103–110. https://doi.org/10.1016/S0008-6363(01)00368-6

    Article  PubMed  Google Scholar 

  55. Zhou H, Ma Q, Zhu P et al (2018) Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy. J Pineal Res 64:e12471

    Article  Google Scholar 

  56. Campanella M, Seraphim A, Abeti R et al (2009) IF1, the endogenous regulator of the F1Fo-ATPsynthase, defines mitochondrial volume fraction in HeLa cells by regulating autophagy. Biochim Biophys Acta Bioenerg 1787:393–401. https://doi.org/10.1016/j.bbabio.2009.02.023

    Article  CAS  Google Scholar 

  57. Campanella M, Parker N, Tan CH et al (2009) IF1: setting the pace of the F1Fo-ATP synthase. Trends Biochem Sci 34:343–350. https://doi.org/10.1016/j.tibs.2009.03.006

    Article  CAS  PubMed  Google Scholar 

  58. Grover GJ, Malm J (2008) Pharmacological profile of the selective mitochondrial F1F 0 ATP hydrolase inhibitor BMS-199264 in myocardial ischemia. Cardiovasc Ther 26:287–296

    Article  CAS  PubMed  Google Scholar 

  59. Atwal KS, Wang P, Rogers WL et al (2004) Small molecule mitochondrial F 1F 0 ATPase hydrolase inhibitors as cardioprotective agents. Identification of 4-(N-Arylimidazole)-Substituted benzopyran derivatives as selective hydrolase inhibitors. J Med Chem 47:1081–1084. https://doi.org/10.1021/jm030291x

    Article  CAS  PubMed  Google Scholar 

  60. Hassinen IE, Vuorinen KH, Ylitalo K, Ala-Rämi A (1998) Role of cellular energetics in ischemia-reperfusion and ischemic preconditioning of myocardium. Mol Cell Biochem 184:393–400

    Article  CAS  PubMed  Google Scholar 

  61. Genoux A, Lichtenstein L, Ferrières J et al (2016) Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES study. BMC Med. https://doi.org/10.1186/s12916-016-0672-9

    Article  PubMed  PubMed Central  Google Scholar 

  62. Burwick NR, Wahl ML, Fang J et al (2005) An inhibitor of the F1 subunit of ATP synthase (IF1) modulates the activity of angiostatin on the endothelial cell surface. J Biol Chem 280:1740–1745. https://doi.org/10.1074/jbc.M405947200

    Article  CAS  PubMed  Google Scholar 

  63. Chapman MJ, Ginsberg HN, Amarenco P et al (2011) Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 32:1345–1361. https://doi.org/10.1093/eurheartj/ehr112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K et al (2011) Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365:2255–2267

    Article  PubMed  Google Scholar 

  65. Barter PJ, Caulfield M, Eriksson M et al (2007) Effects of Torcetrapib in patients at high risk for coronary events. N Engl J Med 357:2109–2122. https://doi.org/10.1056/nejmoa0706628

    Article  CAS  PubMed  Google Scholar 

  66. Martinez LO, Jacquet S, Esteve JP et al (2003) Ectopic β-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 421:75–79. https://doi.org/10.1038/nature01250

    Article  CAS  PubMed  Google Scholar 

  67. Kenan DJ, Wahl ML (2005) Ectopic localization of mitochondrial ATP synthase: a target for anti-angiogenesis intervention? J Bioenerg Biomembr 37:461–465

    Article  CAS  PubMed  Google Scholar 

  68. Fu Y, Zhu Y (2011) Ectopic ATP synthase in endothelial cells: a novel cardiovascular therapeutic target. Curr Pharm Des 16:4074–4079. https://doi.org/10.2174/138161210794519219

    Article  Google Scholar 

  69. Erwin PA, Lin AJ, Golan DE, Michel T (2005) Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 280:19888–19894. https://doi.org/10.1074/jbc.M413058200

    Article  CAS  PubMed  Google Scholar 

  70. Chang HJ, Lee MR, Hong SH et al (2007) Identification of mitochondrial FoF1-ATP synthase involved in liver metastasis of colorectal cancer. Cancer Sci 98:1184–1191. https://doi.org/10.1111/j.1349-7006.2007.00527.x

    Article  CAS  PubMed  Google Scholar 

  71. Ohsakaya S, Fujikawa M, Hisabori T, Yoshida M (2011) Knockdown of DAPIT (diabetes-associated protein in insulin-sensitive tissue) results in loss of ATP synthase in mitochondria. J Biol Chem 286:20292–20296. https://doi.org/10.1074/jbc.M110.198523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pham T, Loiselle D, Power A, Hickey AJR (2014) Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart. Am J Physiol Cell Physiol 307:C499–C507. https://doi.org/10.1152/ajpcell.00006.2014

    Article  CAS  PubMed  Google Scholar 

  73. Ni R, Zheng D, Xiong S et al (2016) Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type 1 diabetic hearts: a novel mechanism contributing to diabetic cardiomyopathy. Diabetes 65:255–268. https://doi.org/10.2337/db15-0963

    Article  CAS  PubMed  Google Scholar 

  74. Zorzano A, Liesa M, Palacin M (2009) Mitochondrial dynamics as a bridge between mitochondrial dysfunction and insulin resistance. Arch Physiol Biochem 115:1–12. https://doi.org/10.1080/13813450802676335

    Article  CAS  PubMed  Google Scholar 

  75. Bach D, Naon D, Pich S et al (2005) Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: Effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α and interleukin-6. Diabetes 54:2685–2693. https://doi.org/10.2337/diabetes.54.9.2685

    Article  CAS  PubMed  Google Scholar 

  76. Johnson A, Ogbi J M (2012) Targeting the F1Fo ATP synthase: modulation of the Bodys powerhouse and its implications for Human Disease. Curr Med Chem 18:4684–4714. https://doi.org/10.2174/092986711797379177

    Article  Google Scholar 

  77. Yang JY, Yeh HY, Lin K, Wang PH (2009) Insulin stimulates akt translocation to mitochondria: implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium. J Mol Cell Cardiol 46:919–926. https://doi.org/10.1016/j.yjmcc.2009.02.015

    Article  CAS  PubMed  Google Scholar 

  78. Stump CS, Short KR, Bigelow ML et al (2003) Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100:7996–8001. https://doi.org/10.1073/pnas.1332551100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rutanen J, Yaluri N, Modi S et al (2010) SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes 59:829–835. https://doi.org/10.2337/db09-1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Victor M, Rocha V, Banuls M C, et al (2011) Mitochondrial dysfunction and targeted drugs: a focus on diabetes. Curr Pharm Des 17:1986–2001. https://doi.org/10.2174/138161211796904722

    Article  CAS  PubMed  Google Scholar 

  81. Schägger H, Ohm TG (2008) Human Diseases with defects in oxidative phosphorylation. Eur J Biochem 227:916–921. https://doi.org/10.1111/j.1432-1033.1995.0916p.x

    Article  Google Scholar 

  82. Kaludercic N, Giorgio V (2016) The dual function of reactive oxygen/nitrogen species in bioenergetics and cell death: the role of ATP synthase. Oxid Med Cell Longev. https://doi.org/10.1155/2016/3869610

    Article  PubMed  PubMed Central  Google Scholar 

  83. Giorgio V, Bisetto E, Franca R et al (2010) The ectopic FOF1 ATP synthase of rat liver is modulated in acute cholestasis by the inhibitor protein IF1. J Bioenerg Biomembr 42:117–123. https://doi.org/10.1007/s10863-010-9270-2

    Article  CAS  PubMed  Google Scholar 

  84. Rosales-Corral SA, Acuña-Castroviejo D, Coto-Montes A et al (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202. https://doi.org/10.1111/j.1600-079X.2011.00937.x

    Article  CAS  PubMed  Google Scholar 

  85. Rotilio G, Aquilano K, Ciriolo MR (2003) Interplay of Cu,Zn Superoxide dismutase and nitric oxide synthase in neurodegenerative processes. IUBMB Life 55:629–634. https://doi.org/10.1080/15216540310001628717

    Article  CAS  PubMed  Google Scholar 

  86. Ahari SE, Houshmand M, Panahi MSS et al (2007) Investigation on mitochondrial tRNALeu/Lys, NDI and ATPase 6/8 in iranian multiple sclerosis patients. Cell Mol Neurobiol 27:695–700. https://doi.org/10.1007/s10571-007-9160-2

    Article  CAS  PubMed  Google Scholar 

  87. Plun-Favreau H, Burchell VS, Holmström KM et al (2012) HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion. Cell Death Dis. https://doi.org/10.1038/cddis.2012.77

    Article  PubMed  PubMed Central  Google Scholar 

  88. Patel BA, D’Amico TL, Blagg BSJ (2020) Natural products and other inhibitors of F1FO ATP synthase. Eur J Med Chem 207:112779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen H (2020) Mitochondria-dependent local caspase activation and mitofusin 2-mediated mitophagy in neurodegeneration. The University of Texas at Dallas, Richardson

    Google Scholar 

  90. Dai W, Jiang L (2019) Dysregulated mitochondrial dynamics and metabolism in obesity, diabetes, and Cancer. Front Endocrinol (Lausanne) 10:570

    Article  PubMed  Google Scholar 

  91. Kong B, Wang Q, Fung E et al (2014) P53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J Biol Chem 289:27134–27145. https://doi.org/10.1074/jbc.M114.594812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wu MX, Ustyugova IV, Han L, Akilov OE (2013) Immediate early response gene X-1, a potential prognostic biomarker in cancers. Expert Opin Ther Targets 17:593–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gore E, Duparc T, Genoux A et al (2022) The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders? Antioxid Redox Signal 37:370–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lippe G, Coluccino G, Zancani M et al (2019) Mitochondrial F-ATP synthase and its transition into an energy-dissipating molecular machine. Oxid Med Cell Longev. https://doi.org/10.1155/2019/8743257

    Article  PubMed  PubMed Central  Google Scholar 

  95. Yang D, Wang MT, Tang Y et al (2010) Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RASQ61L. Cancer Biol Ther 9:122–133. https://doi.org/10.4161/cbt.9.2.10379

    Article  CAS  PubMed  Google Scholar 

  96. Riby JE, Firestone GL, Bjeldanes LF (2008) 3,3′-Diindolylmethane reduces levels of HIF-1α and HIF-1 activity in hypoxic cultured human cancer cells. Biochem Pharmacol 75:1858–1867. https://doi.org/10.1016/j.bcp.2008.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Salomon AR, Voehringer DW, Herzenberg LA, Khosla C (2001) Apoptolidin, a selective cytotoxic agent, is an inhibitor of F0F1-ATPase. Chem Biol 8:71–80. https://doi.org/10.1016/S1074-5521(00)00057-0

    Article  CAS  PubMed  Google Scholar 

  98. Chen I, Hsieh T, Thomas T, Safe S (2001) Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene 262:207–214. https://doi.org/10.1016/S0378-1119(00)00530-8

    Article  CAS  PubMed  Google Scholar 

  99. Shchepina LA, Pletjushkina OY, Avetisyan AV et al (2002) Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis. Oncogene 21:8149–8157. https://doi.org/10.1038/sj.onc.1206053

    Article  CAS  PubMed  Google Scholar 

  100. Wang T, Shen Y, Li Y et al (2019) Ectopic ATP synthase β subunit proteins on human leukemia cell surface interact with platelets by binding glycoprotein IIb. Haematologica 104:e364–e368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Singh S, Khar A (2005) Differential gene expression during apoptosis induced by a serum factor: role of mitochondrial F0-F1 ATP synthase complex. Apoptosis 10:1469–1482. https://doi.org/10.1007/s10495-005-1394-1

    Article  CAS  PubMed  Google Scholar 

  102. Tan DJ, Chang J, Liu LL et al (2006) Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer. BMC Cancer. https://doi.org/10.1186/1471-2407-6-93

    Article  PubMed  PubMed Central  Google Scholar 

  103. Shin YK, Byong CY, Hee JC et al (2005) Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res 65:3162

    Article  CAS  PubMed  Google Scholar 

  104. Sundberg TB, Ney GM, Subramanian C et al (2006) The immunomodulatory benzodiazepine Bz-423 inhibits B-cell proliferation by targeting c-Myc protein for rapid and specific degradation. Cancer Res 66:1775–1782. https://doi.org/10.1158/0008-5472.CAN-05-3476

    Article  CAS  PubMed  Google Scholar 

  105. Johnson KM, Swenson L, Opipari AW et al (2009) Mechanistic basis for differential inhibition of the F1Fo-ATPase by aurovertin. Biopolymers 91:830–840. https://doi.org/10.1002/bip.21262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Rasola A, Bernardi P (2007) The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12:815

    Article  CAS  PubMed  Google Scholar 

  107. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831. https://doi.org/10.1016/j.yjmcc.2009.02.021

    Article  CAS  PubMed  Google Scholar 

  108. Rolo AP, Teodoro JS, Peralta C et al (2009) Prevention of I/R injury in fatty livers by ischemic preconditioning is associated with increased mitochondrial tolerance: the key role of ATPsynthase and mitochondrial permeability transition. Transpl Int 22:1081–1090. https://doi.org/10.1111/j.1432-2277.2009.00916.x

    Article  CAS  PubMed  Google Scholar 

  109. Oliveira CPMS, Da Costa Gayotto LC, Tatai C et al (2002) Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet. J Cell Mol Med 6:399–406. https://doi.org/10.1111/j.1582-4934.2002.tb00518.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Giorgio V, Bisetto E, Soriano ME et al (2009) Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988. https://doi.org/10.1074/jbc.M109.020115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Johnson KM, Chen X, Boitano A et al (2005) Identification and validation of the mitochondrial F1F 0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. Chem Biol 12:485–496. https://doi.org/10.1016/j.chembiol.2005.02.012

    Article  CAS  PubMed  Google Scholar 

  112. Larrick JW, Larrick JW, Mendelsohn AR (2018) ATP synthase, a target for dementia and aging? Rejuvenation Res 21:61–66

    Article  PubMed  Google Scholar 

  113. Armstrong JS (2007) Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br J Pharmacol 151:1154–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Murphy MP (1997) Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol 15:326–330

    Article  CAS  PubMed  Google Scholar 

  115. Pendhari J, Savla H, Bethala D et al (2022) Mitochondria targeted liposomes of metformin for improved anticancer activity: Preparation and evaluation. J Drug Deliv Sci Technol 76:103795. https://doi.org/10.1016/j.jddst.2022.103795

    Article  CAS  Google Scholar 

  116. Devenish RJ, Prescott M, Boyle GM, Nagley P (2000) The oligomycin axis of mitochondrial ATP synthase: OSCP and the proton channel. J Bioenerg Biomembr 32:507–515

    Article  CAS  PubMed  Google Scholar 

  117. Giorgio V, Fogolari F, Lippe G, Bernardi P (2019) OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore. Br J Pharmacol 176:4247–4257. https://doi.org/10.1111/bph.14513

    Article  CAS  PubMed  Google Scholar 

  118. Tan JL, Li F, Yeo JZ et al (2019) New high-throughput screening identifies compounds that reduce viability specifically in liver cancer cells that express high levels of SALL4 by inhibiting oxidative phosphorylation. Gastroenterology 157:1615-1629e17. https://doi.org/10.1053/j.gastro.2019.08.022

    Article  CAS  PubMed  Google Scholar 

  119. Pacheco-Velázquez SC, Robledo-Cadena DX, Hernández-Reséndiz I et al (2018) Energy Metabolism Drugs Block Triple negative breast metastatic Cancer cell phenotype. Mol Pharm 15:2151–2164. https://doi.org/10.1021/acs.molpharmaceut.8b00015

    Article  CAS  PubMed  Google Scholar 

  120. Gale M, Li Y, Cao J et al (2020) Acquired resistance to HER2-targeted therapies creates vulnerability to ATP synthase inhibition. Cancer Res 80:524–535. https://doi.org/10.1158/0008-5472.CAN-18-3985

    Article  CAS  PubMed  Google Scholar 

  121. Zhang J, Cui X, Guo J et al (2020) Small but significant: insights and new perspectives of exosomes in cardiovascular disease. J Cell Mol Med 24:8291–8303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Huang Z, Kondoh E, Visco ZR et al (2021) Targeting dormant ovarian cancer cells in vitro and in an in vivo mouse model of platinum resistance. Mol Cancer Ther 20:85–95. https://doi.org/10.1158/1535-7163.MCT-20-0119

    Article  CAS  PubMed  Google Scholar 

  123. Wender PA, Jankowski OD, Longcore K et al (2006) Correlation of F 0F 1-ATPase inhibition and antiproliferative activity of apoptolidin analogues. Org Lett 8:589–592. https://doi.org/10.1021/ol052800q

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yamashita N, Shin-Ya K, Kitamura M et al (1997) Cytovaricin B, a new inhibitor of JAK-STAT signal transduction produced by Streptomyces torulosus. J Antibot 50:440

    Article  CAS  Google Scholar 

  125. Wang T, Ma F, Qian H (2021) li Defueling the cancer: ATP synthase as an emerging target in cancer therapy. Mol Ther Oncolyt 23:82–95

    Article  CAS  Google Scholar 

  126. Cumero S, Fogolari F, Domenis R et al (2012) Mitochondrial F0F1-ATP synthase is a molecular target of 3-iodothyronamine, an endogenous metabolite of thyroid hormone. Br J Pharmacol 166:2331–2347. https://doi.org/10.1111/j.1476-5381.2012.01958.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chan WK, Tan LTH, Chan KG et al (2016) Nerolidol: a sesquiterpene alcohol with multi-faceted pharmacological and biological activities. Molecules 21:529. https://doi.org/10.3390/molecules21050529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ferreira FM, Palmeira CM, Oliveira MM et al (2012) Nerolidol effects on mitochondrial and cellular energetics. Toxicol Vitr 26:189–196. https://doi.org/10.1016/j.tiv.2011.11.009

    Article  CAS  Google Scholar 

  129. Shi L, Zhang T, Liang X et al (2015) Dihydromyricetin improves skeletal muscle insulin resistance by inducing autophagy via the AMPK signaling pathway. Mol Cell Endocrinol 409:92–102. https://doi.org/10.1016/j.mce.2015.03.009

    Article  CAS  PubMed  Google Scholar 

  130. Hong S, Pedersen PL (2008) ATP synthase and the actions of inhibitors utilized to study its roles in Human Health, Disease, and other scientific areas. Microbiol Mol Biol Rev 72:590–641. https://doi.org/10.1128/mmbr.00016-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Martínez-Reyes I, Sánchez-Aragó M, Cuezva JM (2012) AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. Biochem J 444:249

    Article  PubMed  Google Scholar 

  132. Bergeaud M, Mathieu L, Guillaume A et al (2013) Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F1F0-ATP synthase. Cell Cycle 12:3781–3793. https://doi.org/10.4161/cc.25870

    Article  CAS  Google Scholar 

  133. Terni B, Boada J, Portero-Otin M et al (2010) Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of alzheimer’s disease pathology. Brain Pathol 20:222–233. https://doi.org/10.1111/j.1750-3639.2009.00266.x

    Article  CAS  PubMed  Google Scholar 

  134. Chang HY, Huang TC, Chen NN et al (2014) Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. Cell Death Dis 5:e1540–e1540. https://doi.org/10.1038/cddis.2014.504

    Article  PubMed  PubMed Central  Google Scholar 

  135. Papathanassiu AE, MacDonald NJ, Emlet DR, Vu HA (2011) Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo. Cell Stress Chaperones 16:181–193. https://doi.org/10.1007/s12192-010-0231-9

    Article  CAS  PubMed  Google Scholar 

  136. Andries K, Verhasselt P, Guillemont J et al (2005) A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307:223–227. https://doi.org/10.1126/science.1106753

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India

    Varsha Singh

Authors
  1. Varsha Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Varsha Singh conceived the idea and wrote the manuscript.

Corresponding author

Correspondence to Varsha Singh.

Ethics declarations

Conflict of interest

Author declares no conflict of interest.

Consent to participate

This article does not contain any studies with human participants or animals performed by the author.

Consent to publish

This article does not contain any studies with human participants or animals performed by the author.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, V. F1Fo adenosine triphosphate (ATP) synthase is a potential drug target in non-communicable diseases. Mol Biol Rep 50, 3849–3862 (2023). https://doi.org/10.1007/s11033-023-08299-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-023-08299-3

Keywords

Search

Navigation