Cell Biology and Toxicology

, Volume 29, Issue 6, pp 407–414 | Cite as

FK506 affects mitochondrial protein synthesis and oxygen consumption in human cells

  • María Palacín
  • Eliecer Coto
  • Laura Llobet
  • David Pacheu-Grau
  • Julio Montoya
  • Eduardo Ruiz-Pesini
Original Research


FK506 is an important immunosuppressive medication. However, it can provoke neurotoxicity, nephrotoxicity, and diabetes as adverse side effects. The decrease in oxygen consumption of rat cells treated with pharmacologically relevant concentrations of FK506, along with other evidences, has insinuated that some of the toxic effects are probably caused by drug-induced mitochondrial dysfunction at the level of gene expression. To confirm this suggestion, we have analyzed cell respiration and mitochondrial protein synthesis in human cell lines treated with FK506. This drug provokes an important decrease in oxygen consumption, accompanied by a slight reduction in the synthesis of mitochondria DNA-encoded proteins. These results are similar to those triggered by rapamycin, another macrolide with immunosuppressive properties, therefore insinuating a common toxic pathway.


FK506 Mitochondria Oxidative phosphorylation Toxicity 



This work was supported by grants from Instituto de Salud Carlos III [FIS-PI10/00662, PI11/01301, REDINREN-RD06/0016]; Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón y Fondo Social Europeo [Grupos Consolidados B33]; and FEDER Funding Program from the European Union. DP-G was supported by the Asociación de Enfermos de Patología Mitocondrial (AEPMI). MP and LL have fellowships from FICYT-Principado de Asturias and Instituto de Salud Carlos III (FI12/00217), respectively. The CIBERER is an initiative of the ISCIII.


  1. Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landazuri MO, et al. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 2012;16:378–86.PubMedCrossRefGoogle Scholar
  2. Bottiger Y, Brattstrom C, Tyden G, Sawe J, Groth CG. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol. 1999;48:445–8.PubMedCrossRefGoogle Scholar
  3. Chomyn A. In vivo labeling and analysis of human mitochondrial translation products. Methods Enzymol. 1996;264:197–211.PubMedGoogle Scholar
  4. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–40.PubMedCrossRefGoogle Scholar
  5. Doersen CJ, Stanbridge EJ. Cytoplasmic inheritance of erythromycin resistance in human cells. Proc Natl Acad Sci U S A. 1979;76:4549–53.PubMedCrossRefGoogle Scholar
  6. Doersen CJ, Stanbridge EJ. Erythromycin inhibition of cell proliferation and in vitro mitochondrial protein synthesis in human HeLa cells is pH dependent. Biochim Biophys Acta. 1982;698:62–9.PubMedCrossRefGoogle Scholar
  7. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant rapamycin. Life Sci. 1996;58:373–95.PubMedCrossRefGoogle Scholar
  8. Gomez-Duran A, Pacheu-Grau D, Lopez-Gallardo E, Diez-Sanchez C, Montoya J, Lopez-Perez MJ, et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum Mol Genet. 2010;19:3343–53.PubMedCrossRefGoogle Scholar
  9. Illsinger S, Goken C, Brockmann M, Thiemann I, Bednarczyk J, Schmidt KH, et al. Effect of tacrolimus on energy metabolism in human umbilical endothelial cells. Ann Transplant. 2011;16:68–75.PubMedGoogle Scholar
  10. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot. 1987;40:1249–55 (Tokyo).PubMedCrossRefGoogle Scholar
  11. Krentz AJ, Dousset B, Mayer D, McMaster P, Buckels J, Cramb R, et al. Metabolic effects of cyclosporin A and FK 506 in liver transplant recipients. Diabetes. 1993;42:1753–59.PubMedCrossRefGoogle Scholar
  12. Luca CC, Lam BL, Moraes CT. Erythromycin as a potential precipitating agent in the onset of Leber's hereditary optic neuropathy. Mitochondrion. 2004;4:31–6.PubMedCrossRefGoogle Scholar
  13. Luo Y, Rana P, Will Y. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells. Toxicol Appl Pharmacol. 2012;261:172–80.PubMedCrossRefGoogle Scholar
  14. Madsen KL, Yanchar NL, Sigalet DL, Reigel T, Fedorak RN. FK506 increases permeability in rat intestine by inhibiting mitochondrial function. Gastroenterology. 1995;109:107–14.PubMedCrossRefGoogle Scholar
  15. Martínez-Romero I, Emperador S, Llobet L, Montoya J, Ruiz-Pesini E. Mitogenomics: recognizing the significance of mitochondrial genomic variation for personalized medicine. Curr Pharmacogenomics Pers Med. 2011;9:84–93.CrossRefGoogle Scholar
  16. Moreno-Loshuertos R, Ferrin G, Acin-Perez R, Gallardo ME, Viscomi C, Perez-Martos A, et al. Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. PLoS Genet. 2011;7:e1001379.PubMedCrossRefGoogle Scholar
  17. Prokai A, Fekete A, Pasti K, Rusai K, Banki NF, Reusz G, et al. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes. 2012;13:81–91.PubMedCrossRefGoogle Scholar
  18. Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A. 2009;106:22229–32.PubMedCrossRefGoogle Scholar
  19. Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T. Mitochondrial threshold effects. Biochem J. 2003;370:751–62.PubMedCrossRefGoogle Scholar
  20. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004;64:985–93.PubMedCrossRefGoogle Scholar
  21. Rostambeigi N, Lanza IR, Dzeja PP, Deeds MC, Irving BA, Reddi HV, et al. Unique cellular and mitochondrial defects mediate FK506-induced islet beta-cell dysfunction. Transplantation. 2011;91:615–23.PubMedCrossRefGoogle Scholar
  22. Ruiz-Pesini E, Diez C, Lapena AC, Perez-Martos A, Montoya J, Alvarez E, et al. Correlation of sperm motility with mitochondrial enzymatic activities. Clin Chem. 1998;44:1616–20.PubMedGoogle Scholar
  23. Schieke SM, Phillips D, McCoy Jr JP, Aponte AM, Shen RF, Balaban RS, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006;281:27643–52.PubMedCrossRefGoogle Scholar
  24. Serkova N, Christians U. Transplantation: toxicokinetics and mechanisms of toxicity of cyclosporine and macrolides. Curr Opin Investig Drugs. 2003;4:1287–96.PubMedGoogle Scholar
  25. Simon N, Morin C, Urien S, Tillement JP, Bruguerolle B. Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria. Br J Pharmacol. 2003;138:369–76.PubMedCrossRefGoogle Scholar
  26. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000–4.PubMedCrossRefGoogle Scholar
  27. Thorburn DR, Rahman S. Mitochondrial DNA-associated Leigh syndrome and NARP. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K (eds) GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2013. 2003 Oct 30 [updated 2011 May 3].Google Scholar
  28. Trounce I, Neill S, Wallace DC. Cytoplasmic transfer of the mtDNA nt 8993 T->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc Natl Acad Sci U S A. 1994;91:8334–8.PubMedCrossRefGoogle Scholar
  29. Van der Poel HG, Hanrahan C, Zhong H, Simons JW. Rapamycin induces Smad activity in prostate cancer cell lines. Urol Res. 2003;30:380–6.PubMedGoogle Scholar
  30. Vijayasarathy C, Raza H, Avadhani NG. Inhibition of mitochondrial translation by calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. Biochim Biophys Acta. 1993;1143:38–44.PubMedCrossRefGoogle Scholar
  31. Yu JJ, Zhang Y, Wang Y, Wen ZY, Liu XH, Qin J, et al. Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl). 2013;225:361–72.CrossRefGoogle Scholar
  32. Zamorano-Leon JJ, Lopez-Farre AJ, Marques M, Rodriguez P, Modrego J, Segura A, et al. Changes by tacrolimus of the rat aortic proteome: involvement of endothelin-1. Transpl Immunol. 2012;26:191–200.PubMedCrossRefGoogle Scholar
  33. Zini R, Simon N, Morin C, Thiault L, Tillement JP. Tacrolimus decreases in vitro oxidative phosphorylation of mitochondria from rat forebrain. Life Sci. 1998;63:357–68.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • María Palacín
    • 1
    • 4
  • Eliecer Coto
    • 1
    • 2
    • 3
  • Laura Llobet
    • 4
  • David Pacheu-Grau
    • 4
  • Julio Montoya
    • 4
  • Eduardo Ruiz-Pesini
    • 4
    • 5
    • 6
  1. 1.Genética MolecularHospital Universitario Central de Asturias (HUCA)OviedoSpain
  2. 2.Departamento de MedicinaUniversidad de OviedoOviedoSpain
  3. 3.Fundación Renal I. Alvarez de ToledoMadridSpain
  4. 4.Departamento de Bioquímica Biología Molecular y Celular and Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER)ZaragozaSpain
  5. 5.Fundación ARAIDUniversidad de ZaragozaZaragozaSpain
  6. 6.Departamento de Bioquímica, Biología Molecular y CelularUniversidad de ZaragozaZaragozaSpain

Personalised recommendations