Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as macroenzyme creatine kinase type 2 (macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear.
Methods
A prospective observational 5-year follow-up study was performed on those patients in which macro CK2 appearance was initially described (‘TDF switch study’ cohort). In addition, tenofovir (TFV), its prodrug TDF and its active, intracellular derivative TFV diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds.
Results
In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) originally positive patients were macro CK2-negative at the end of follow-up. Prospective clinical follow-up data indicate that macro CK2 appearance under TDF is not associated with significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions.
Conclusions
Appearance of octameric uMtCK as macro CK2 in the serum of TDF-treated patients is suggested to result from a combination of low-level mitochondrial damage caused by subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.
References
1.
LeeK.N., CsakoG., BernhardtP., ElinR.J.Relevance of macro creatine kinase type 1 and type 2 isoenzymes to laboratory and clinical data. Clin Chem1994; 40: 1278–1283.
2.
SchmidH., MühlbayerD., RölingJ.Macroenzyme creatine kinase (CK) type 2 in HIV-infected patients is significantly associated with TDF and consists of ubiquitous mitochondrial CK. Antivir Ther2006; 11: 1071–1080.
3.
QinW., KhuchuaZ., ChengJ., BoeroJ., PayneR.M., StraussA.W.Molecular characterization of the creatine kinases and some historical perspectives. Mol Cell Biochem1998; 184: 153–167.
4.
SchlattnerU., Tokarska-SchlattnerM., WallimannT.Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta2006; 1762: 164–180.
5.
WallimannT., HemmerW.Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem1994; 133–134: 193–220.
6.
WallimannT., Tokarska-SchlattnerM., SchlattnerU.The creatine kinase system and pleiotropic effects of creatine. Amino Acids2011; 40: 1271–1296.
7.
NeumannD., SchlattnerU., WallimannT.A molecular approach to the concerted action of kinases involved in energy homeostasis. Biochem Soc Trans2003; 31: 169–174.
8.
SobollS., BrdiczkaD., JahnkeD.Octamer-dimer transitions of mitochondrial creatine kinase in heart muscle. J Mol Cell Cardiol1999; 31: 857–866.
9.
Tokarska-SchlattnerM., ZauggM., da SilvaR.Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am J Physiol Heart Circ Physiol2005; 289: H37–H47.
10.
Tokarska-SchlattnerM., DolderM., GerberI., SpeerO., WallimannT., SchlattnerU.Reduced creatine stimulated respiration in doxorubicin challenged mitochondria: particular sensitivity of the heart. Biochim Biophys Acta2007; 1767: 1276–1284.
11.
SchlattnerU., WallimannT.Octamers of mitochondrial creatine kinase differ in stability and membrane binding. J Biol Chem2000; 275: 17314–17320.
12.
KochK., ChenY.X., FengJ.Y.Nucleoside diphosphate kinase and the activation of antiviralphosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovirderivatives. Nucleosides Nucleotides Nucleic Acids2009; 28: 776–792.
13.
JohnsonA.A., RayA.S., HanesJ.Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem2001; 276: 40847–40857.
14.
Rodriguez-NóvoaS., AlvarezE., LabargaP., SorianoV.Renal toxicity associated with tenofovir use. Expert Opin Drug Saf2010; 9: 545–559.
CooperR.D., TonelliM.Renal disease associated with antiretroviral therapy in the treatment of HIV. Nephron Clin Pract2011; 118: c262–c268.
17.
Fernandez-FernandezB., Montoya-FerrerA., SanzA.B.Tenofovir nephrotoxicity: 2011 update. Aids Res Treat2011; 2011: 354908.
18.
ClaasG.J., JülgB., GoebelF.D., BognerJ.R.Metabolic and anthropometric changes one year after switching from didanosine/stavudine to tenofovir in HIV-infected patients. Eur J Med Res2007; 12: 54–60.
19.
StevensL.A., CoreshJ., GreeneT., LeveyA.S.Assessing kidney function–measured and estimated glomerular filtration rate. N Engl J Med2006; 354: 2473–2483.
20.
CockcroftD.W., GaultM.H.Prediction of creatinine clearance from serum creatinine. Nephron1976; 16: 31–41.
21.
SchlattnerU., EderM., DolderM., KhuchuaZ.A., StraussA.W., WallimannT.Divergent enzyme kinetics and structural properties of the two human mitochondrial creatine kinase isoenzymes. Biol Chem2000; 381: 1063–1070.
22.
SchlattnerU., ReinhartC., HornemannT., Tokarska-SchlattnerM., WallimannT.Single chain Fv antibodies directed against cytosolic creatine kinase isolated from a synthetic human phage display library. Biochim Biophys Acta2002; 1579: 124–132.
23.
Tokarska-SchlattnerM., BoissanM., MunierA.The nucleoside diphosphate kinase D (nm23-H4) binds the mitochondrial inner membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration. J Biol Chem2008; 283: 26198–26207.
24.
WallimannT., SchlösserT., EppenbergerH.M.Function of M-line-bound creatine kinase as intramyofibrillar ATP regenerator at the receiving end of thephosphorylcreatine shuttle in muscle. J Biol Chem1984; 259: 5238–5246.
25.
EderM., Fritz-WolfK., KabschW., WallimannT., SchlattnerU.Crystal structure of human ubiquitous creatine kinase. Proteins2000; 39: 216–225.
26.
Tokarska-SchlattnerM., WallimannT., SchlattnerU.Multiple interference of anthracyclines with mitochondrial creatine kinases: preferential damage of the cardiac isoenzyme and its implications for drug cardiotoxicity. Mol Pharmacol2002; 61: 516–523.
27.
NeumannD., WoodsA., CarlingD., WallimannT., SchlattnerU.Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expr Purif2003; 30: 230–237.
28.
SteinW., BohnerJ., RennW., MaulbetschR.Macro creatine kinase type 2: results of a prospective study in hospitalized patients. Clin Chem1985; 31: 1959–1964.
29.
MercerD.W., TalamoT.S.Multiple markers of malignancy in sera of patients with colorectal carcinoma: preliminary clinical studies. Clin Chem1985; 31: 1824–1828.
30.
KiserJ.J., AquilanteC.L., AndersonP.L., KingT.M., CartenM.L., FletcherC.V.Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr2008; 47: 298–303.
31.
MillarI.D., HartleyJ.A., HaighC.Volume regulation is defective in renal proximal tubule cells isolated from KCNE1 knockout mice. Exp Physiol2004; 89: 173–180.
LeeH., HanesJ., JohnsonK.A.Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry2003; 42: 14711–14719.
GuerreroM.L., BeronJ., SpindlerB., GroscurthP., WallimannT., VerreyF.Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase. Am J Physiol1997; 272: C697–C706.
CooperR.D., WiebeN., SmithN., KeiserP., NaickerS., TonelliM.Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis2010; 51: 496–505.
39.
MocroftA., KirkO., ReissP.Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS2010; 24: 1667–1678.
40.
VrouenraetsS.M., FuxC.A., WitF.W.Persistent decline in estimated but not measured glomerular filtration rate on tenofovir may refect tubular rather than glomerular toxicity. AIDS2011; 25: 2149–2155.
41.
VrouenraetsS.M., FuxC.A., WitF.W.A comparison of measured and estimated glomerular filtration rate in successfully treated HIV-patients with preserved renal function. Clin Nephrol2012; 77: 311–320.
42.
AlbiniL., CesanaB.M., MottaD.A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naive HIV-infected patients after tenofovir/ emtricitabine in combination with atazanavir/ritonavir or efavirenz. J Acquir Immune Defic Syndr2012; 59: 18–30.
LabargaP., BarreiroP., Martin-CarboneroL.Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS2009; 23: 689–696.
45.
BuchaczK., YoungB., BakerR.K.Renal function in patients receiving tenofovir with ritonavir/lopinavir or ritonavir/atazanavir in the HIV Outpatient Study (HOPS) cohort. J Acquir Immune Defic Syndr2006; 43: 626–628.
46.
BadiouS., De BoeverC.M., TerrierN., BaillatV., CristolJ.P., ReynesJ.Is tenofovir involved in hypophosphatemia and decrease of tubular phosphate reabsorption in HIV-positive adults?J Infect2006; 52: 335–338.
47.
AndoM., YanagisawaN., AjisawaA., TsuchiyaK., NittaK.Kidney tubular damage in the absence of glomerular defects in HIV-infected patients on highly active antiretroviral therapy. Nephrol Dial Transplant2011; 26: 3224–3229.
48.
WatanabeD., YoshinoM., YaguraH.Increase in serum mitochondrial creatine kinase levels induced by tenofovir administration. J Infect Chemother2012; 18: 675–682.
49.
TarnopolskyM.A., ParshadA., WalzelB., SchlattnerU., WallimannT.Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve2001; 24: 682–688.
50.
StadhoudersA.M., JapP.H., WinklerH.P., EppenbergerH.M., WallimannT.Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies. Proc Natl Acad Sci U S A1994; 91: 5089–5093.
51.
DeLucaM., HallN., RiceR., KaplanN.O.Creatine kinase isozymes in human tumors. Biochem Biophys Res Commun1981; 99: 189–195.
52.
PrattR., VallisL.M., LimC.W., ChisnallW.N.Mitochondrial creatine kinase in cancer patients. Pathology1987; 19: 162–165.
53.
KornackerM., SchlattnerU., WallimannT.Hodgkin disease-derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis. Int J Cancer2001; 94: 513–519.
54.
SobollS., BrdiczkaD., JahnkeD.Octamer-dimer transitions of mitochondrial creatine kinase in heart disease. J Mol Cell Cardiol1999; 31: 857–866.
55.
WendtS., SchlattnerU., WallimannT.Differential effects of peroxynitrate on human mitochondrial creatine kinase isoenzymes: Inactivation and octamer destabilzation. J Biol Chem2003; 278: 1125–1130.
56.
AwamaA.M., MazonH., VialC., MarcillatO.Despite its high similarity with monomeric arginine kinase, muscle creatine kinase is only enzymatically active as a dimer. Arch Biochem Biophys2007; 458: 158–166.
57.
O'GormanE., BeutnerG., DolderM., KoretskyA.P., BrdiczkaD., WallimannT.The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett1997; 414: 253–257.
58.
SchlattnerU., ForstnerM., EderM., StachowiakO., Fritz-WolfK., WallimannT.Functional aspects of the X-ray structure of mitochondrial creatine kinase: a molecular physiology approach. Mol Cell Biochem1998; 184: 125–140.
