Abstract
Purpose
Excess production of reactive oxygen species (ROS) from the mitochondria can promote mitochondrial dysfunction and has been implicated in the development of a range of chronic diseases. As such there is interest in whether mitochondrial-targeted antioxidant supplementation can attenuate mitochondrial-associated oxidative stress. We investigated the effect of MitoQ and CoQ10 supplementation on oxidative stress and skeletal muscle mitochondrial ROS levels and function in healthy middle-aged men.
Methods
Skeletal muscle and blood samples were collected from twenty men (50 ± 1 y) before and following six weeks of daily supplementation with MitoQ (20 mg) or CoQ10 (200 mg). High-resolution respirometry was used to determine mitochondrial respiration and H2O2 levels, markers of mitochondrial mass and antioxidant defences were measured in muscle samples and oxidative stress markers in urine and blood samples.
Results
Both MitoQ and CoQ10 supplementation suppressed mitochondrial net H2O2 levels during leak respiration, while MitoQ also elevated muscle catalase expression. However, neither supplement altered urine F2-isoprostanes nor plasma TBARS levels. Neither MitoQ nor CoQ10 supplementation had a significant impact on mitochondrial respiration or mitochondrial density markers (citrate synthase, mtDNA/nDNA, PPARGC1A, OXPHOS expression).
Conclusion
Our results suggest that neither MitoQ and CoQ10 supplements impact mitochondrial function, but both can mildly suppress mitochondrial ROS levels in healthy middle-aged men, with some indication that MitoQ may be more effective than CoQ10.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- BCA:
-
Bicinchoninic acid assay
- CI-IV:
-
Complex 1–4
- CAT:
-
Catalase
- CoQ10:
-
Coenzyme Q10
- CCO:
-
Cytochrome C oxidase
- CS:
-
Citrate synthase
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- H2O2 :
-
Hydrogen peroxide
- LSD:
-
Fisher's least significant difference
- MES:
-
2-(N-morpholino)ethanesulfonic acid
- OXPHOS:
-
Oxidative phosphorylation
- O2 :
-
Oxygen
- RIPA:
-
Radioimmunoprecipitation assay buffer
- ROS:
-
Reactive oxygen species
- SDS-PAGE:
-
Sodium dodecyl sulphate–polyacrylamide gel electrophoresis
- SOD:
-
Superoxide dismutase
- TBARS:
-
Thiobarbituric acid-reactive substances
- TPP+ :
-
Triphenylphosphonium
References
Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA (2005) Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 19(9):1088–1095. https://doi.org/10.1096/fj.05-3718com
Alcazar-Fabra M, Navas P, Brea-Calvo G (2016) Coenzyme Q biosynthesis and its role in the respiratory chain structure. Biochim Biophys Acta. https://doi.org/10.1016/j.bbabio.2016.03.010
Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochem Mosc 70:200–214
Anson RM, Bohr VA (2000) Mitochondria, oxidative DNA damage, and aging. J Am Aging Assoc 23(4):199–218. https://doi.org/10.1007/s11357-000-0020-y
Baraibar MA, Liu L, Ahmed EK, Friguet B (2012) Protein oxidative damage at the crossroads of cellular senescence, aging, and age-related diseases. Oxid Med Cell Longev 2012:919832. https://doi.org/10.1155/2012/919832
Barden A, Mori TA (2018) GC-MS analysis of autoxidation products in blood and tissue samples. In: Giera M (ed) Clinical metabolomics: methods and protocols. Springer Science Business Media, New York, pp 283–292
Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78(2):547–581. https://doi.org/10.1152/physrev.1998.78.2.547
Bond ST, Kim J, Calkin AC, Drew BG (2019) The Antioxidant moiety of MitoQ imparts minimal metabolic effects in adipose tissue of high fat fed mice. Front Physiol 10:543. https://doi.org/10.3389/fphys.2019.00543
Braakhuis AJ, Nagulan R, Somerville V (2018) The effect of MitoQ on aging-related biomarkers: a systematic review and meta-analysis. Oxid Med Cell Longev 2018:8575263. https://doi.org/10.1155/2018/8575263
Brauner H, Lüthje P, Grünler J, Ekberg NR, Dallner G, Brismar K, Brauner A (2014) Markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the anti-oxidant coenzyme Q10 on inflammatory activity. Clin Exp Immunol 177(2):478–482. https://doi.org/10.1111/cei.12316
Broome SC, Woodhead JST, Merry TL (2018) Mitochondria-targeted antioxidants and skeletal muscle function. Antioxidants (Basel). https://doi.org/10.3390/antiox7080107
Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV (2014) Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014:238463. https://doi.org/10.1155/2014/238463
Chun OK, Floegel A, Chung SJ, Chung CE, Song WO, Koo SI (2010) Estimation of antioxidant intakes from diet and supplements in US adults. J Nutr 140(2):317–324. https://doi.org/10.3945/jn.109.114413
Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354. https://doi.org/10.1155/2012/646354
Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, Ngo CP, Prolla TA, Rabinovitch PS (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9(4):536–544. https://doi.org/10.1111/j.1474-9726.2010.00581.x
Draeger CL, Naves A, Marques N, Baptistella AB, Carnauba RA, Paschoal V, Nicastro H (2014) Controversies of antioxidant vitamins supplementation in exercise: ergogenic or ergolytic effects in humans? J Int Soc Sports Nutr 11(1):4. https://doi.org/10.1186/1550-2783-11-4
Fallah M, Askari G, Soleimani A, Feizi A, Asemi Z (2018) Clinical trial of the effects of coenzyme Q10 supplementation on glycemic control and markers of lipid profiles in diabetic hemodialysis patients. Int Urol Nephrol 50(11):2073–2079. https://doi.org/10.1007/s11255-018-1973-z
Feillet-Coudray C, Fouret G, Ebabe Elle R, Rieusset J, Bonafos B, Chabi B, Crouzier D, Zarkovic K, Zarkovic N, Ramos J, Badia E, Murphy MP, Cristol JP, Coudray C (2014) The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than Apocynin or Allopurinol. Free Radic Res 48(10):1232–1246. https://doi.org/10.3109/10715762.2014.945079
Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194(1):7–15. https://doi.org/10.1083/jcb.201102095
Fock E, Bachteeva V, Lavrova E, Parnova R (2018) Mitochondrial-targeted antioxidant MitoQ prevents E. coli lipopolysaccharide-induced accumulation of triacylglycerol and lipid droplets biogenesis in epithelial cells. J Lipids 2018:5745790. https://doi.org/10.1155/2018/5745790
Forman HJ, Augusto O, Brigelius-Flohe R, Dennery PA, Kalyanaraman B, Ischiropoulos H, Mann GE, Radi R, Roberts LJ 2nd, Vina J, Davies KJ (2015) Even free radicals should follow some rules: a guide to free radical research terminology and methodology. Free Radic Biol Med 78:233–235. https://doi.org/10.1016/j.freeradbiomed.2014.10.504
Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM, Frampton CM, Taylor KM, Smith RA, Murphy MP (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int 30(7):1019–1026. https://doi.org/10.1111/j.1478-3231.2010.02250.x
Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cocheme HM, Murphy MP, Dominiczak AF (2009) Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 54(2):322–328. https://doi.org/10.1161/hypertensionaha.109.130351
Greenberg S, Frishman WH (1990) Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 30(7):596–608. https://doi.org/10.1002/j.1552-4604.1990.tb01862.x
Hedges CP, Woodhead JST, Wang HW, Mitchell CJ, Cameron-Smith D, Hickey AJR, Merry TL (2019) Peripheral blood mononuclear cells do not reflect skeletal muscle mitochondrial function or adaptation to high-intensity interval training in healthy young men. J Appl Physiol 126(2):454–461. https://doi.org/10.1152/japplphysiol.00777.2018
Hulsmans M, Van Dooren E, Holvoet P (2012) Mitochondrial reactive oxygen species and risk of atherosclerosis. Curr Atheroscler Rep 14(3):264–276. https://doi.org/10.1007/s11883-012-0237-0
Hwang AB, Jeong DE, Lee SJ (2012) Mitochondria and organismal longevity. Curr Genom 13(7):519–532. https://doi.org/10.2174/138920212803251427
James AM, Cocheme HM, Smith RA, Murphy MP (2005) Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem 280(22):21295–21312. https://doi.org/10.1074/jbc.M501527200
Kikusato M, Nakamura K, Mikami Y, Mujahid A, Toyomizu M (2016) The suppressive effect of dietary coenzyme Q10 on mitochondrial reactive oxygen species production and oxidative stress in chickens exposed to heat stress. Anim Sci J 87(10):1244–1251. https://doi.org/10.1111/asj.12543
Kulkarni MM (2011) Digital multiplexed gene expression analysis using the nano string ncounter system. Curr Protoc Mol Biol. https://doi.org/10.1002/0471142727.mb25b10s94
Lane RK, Hilsabeck T, Rea SL (2015) The role of mitochondrial dysfunction in age-related diseases. Biochim Biophys Acta 11:1387–1400. https://doi.org/10.1016/j.bbabio.2015.05.021
Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI (2010) Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 12(6):668–674. https://doi.org/10.1016/j.cmet.2010.11.004
Lee BJ, Huang YC, Chen SJ, Lin PT (2012) Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition 28(3):250–255. https://doi.org/10.1016/j.nut.2011.06.004
Lee BJ, Tseng YF, Yen CH, Lin PT (2013) Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial. Nutr J 12(1):142. https://doi.org/10.1186/1475-2891-12-142
Littarru GP, Tiano L (2007) Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol 37(1):31–37. https://doi.org/10.1007/s12033-007-0052-y
Luo K, Yu JH, Quan Y, Shin YJ, Lee KE, Kim HL, Ko EJ, Chung BH, Lim SW, Yang CW (2019) Therapeutic potential of coenzyme Q10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury. Sci Rep 9(1):7995. https://doi.org/10.1038/s41598-019-44475-x
Margaritelis NV, Paschalis V, Theodorou AA, Kyparos A, Nikolaidis MG (2018) Antioxidants in personalized nutrition and exercise. Adv Nutr 9(6):813–823. https://doi.org/10.1093/advances/nmy052
Maroz A, Anderson RF, Smith RA, Murphy MP (2009) Reactivity of ubiquinone and ubiquinol with superoxide and the hydroperoxyl radical: implications for in vivo antioxidant activity. Free Radic Biol Med 46(1):105–109. https://doi.org/10.1016/j.freeradbiomed.2008.09.033
McManus MJ, Murphy MP, Franklin JL (2011) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J Neurosci 31(44):15703–15715. https://doi.org/10.1523/jneurosci.0552-11.2011
Murphy M (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
Murphy M, Smith RA (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656. https://doi.org/10.1146/annurev.pharmtox.47.120505.105110
Nakazawa H, Ikeda K, Shinozaki S, Yasuhara S, Yu YM, Martyn JAJ, Tompkins RG, Yorozu T, Inoue S, Kaneki M (2019) Coenzyme Q10 protects against burn-induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle. FEBS Open Bio 9(2):348–363. https://doi.org/10.1002/2211-5463.12580
Nishikawa T, Kukidome D, Sonoda K, Fujisawa K, Matsuhisa T, Motoshima H, Matsumura T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of insulin resistance. Diabetes Res Clin Pract 77(Suppl 1):S161–164
Noh YH, Kim KY, Shim MS, Choi SH, Choi S, Ellisman MH, Weinreb RN, Perkins GA, Ju WK (2013) Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis 4:e820. https://doi.org/10.1038/cddis.2013.341
O'Malley Y, Fink BD, Ross NC, Prisinzano TE, Sivitz WI (2006) Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem 281(52):39766–39775. https://doi.org/10.1074/jbc.M608268200
Paschalis V, Theodorou AA, Margaritelis NV, Kyparos A, Nikolaidis MG (2018) N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione. Free Radic Biol Med 115:288–297. https://doi.org/10.1016/j.freeradbiomed.2017.12.007
Pham T, Loiselle D, Power A, Hickey A (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
Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30(1):11–26. https://doi.org/10.1007/s12291-014-0446-0
Powell RD, Swet JH, Kennedy KL, Huynh TT, Murphy MP, McKillop IH, Evans SL (2015) MitoQ modulates oxidative stress and decreases inflammation following hemorrhage. J Trauma Acute Care Surg 78(3):573–579. https://doi.org/10.1097/ta.0000000000000533
Powers SK, Jackson MJ (2008) Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 88(4):1243–1276. https://doi.org/10.1152/physrev.00031.2007
Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20(7):709–711. https://doi.org/10.1038/nm.3624
Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327–336
Ross MF, Kelso GF, Blaikie FH, James AM, Cocheme HM, Filipovska A, Da Ros T, Hurd TR, Smith RA, Murphy MP (2005) Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc) 70(2):222–230. https://doi.org/10.1007/s10541-005-0104-5
Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, Woodward KA, Chonchol M, Gioscia-Ryan RA, Murphy MP, Seals DR (2018) Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 71(6):1056–1063. https://doi.org/10.1161/hypertensionaha.117.10787
Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–462. https://doi.org/10.1016/j.cub.2014.03.034
Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308(5730):1909–1911. https://doi.org/10.1126/science.1106653
Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91(23):10771–10778. https://doi.org/10.1073/pnas.91.23.10771
Shill DD, Southern WM, Willingham TB, Lansford KA, McCully KK, Jenkins NT (2016) Mitochondria-specific antioxidant supplementation does not influence endurance exercise training-induced adaptations in circulating angiogenic cells, skeletal muscle oxidative capacity or maximal oxygen uptake. J Physiol 594(23):7005–7014. https://doi.org/10.1113/JP272491
Smith RA, Porteous CM, Coulter CV, Murphy MP (1999) Selective targeting of an antioxidant to mitochondria. Eur J Biochem 263(3):709–716. https://doi.org/10.1046/j.1432-1327.1999.00543.x
Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM, Protect Study G (2010) A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord 25(11):1670–1674. https://doi.org/10.1002/mds.2314A8
Sohal RS, Kamzalov S, Sumien N, Ferguson M, Rebrin I, Heinrich KR, Forster MJ (2006) Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice. Free Radic Biol Med 40(3):480–487. https://doi.org/10.1016/j.freeradbiomed.2005.08.037
Szeto HH (2008) Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 10(3):601–619. https://doi.org/10.1089/ars.2007.1892
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(Pt 2):335–344. https://doi.org/10.1113/jphysiol.2003.049478
Varela-López A, Giampieri F, Battino M, Quiles JL (2016) Coenzyme Q and its role in the dietary therapy against aging. Molecules 21(3):373. https://doi.org/10.3390/molecules21030373
Vincent G, Lamon S, Gant N, Vincent PJ, MacDonald JR, Markworth JF, Edge JA, Hickey AJ (2015) Changes in mitochondrial function and mitochondria associated protein expression in response to 2-weeks of high intensity interval training. Front Physiol 6:51. https://doi.org/10.3389/fphys.2015.00051
Wallace DC (2001) Mitochondrial defects in neurodegenerative disease. Ment Retard Dev Disabil Res Rev 7(3):158–166. https://doi.org/10.1002/mrdd.1023
Weimer S, Priebs J, Kuhlow D, Groth M, Priebe S, Mansfeld J, Merry TL, Dubuis S, Laube B, Pfeiffer AF, Schulz TJ, Guthke R, Platzer M, Zamboni N, Zarse K, Ristow M (2014) D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat Commun 5:3563. https://doi.org/10.1038/ncomms4563
Wray DW, Nishiyama SK, Harris RA, Zhao J, McDaniel J, Fjeldstad AS, Witman MA, Ives SJ, Barrett-O'Keefe Z, Richardson RS (2012) Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension 59(4):818–824. https://doi.org/10.1161/hypertensionaha.111.189456
Yin X, Manczak M, Reddy PH (2016) Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease. Hum Mol Genet 25(9):1739–1753. https://doi.org/10.1093/hmg/ddw045
Acknowledgements
We are thankful to all participants for their contribution to the study. We would like to acknowledge Dr’s Karina McKearney, Jacob Rollo and Ryan Yeu for their practical assistance in the biopsy procedure. We also appreciate Shannon Adams for her technical support. TLM is supported by a Rutherford Discovery Fellowship.
Funding
This study was financially supported by MitoQ®. MitoQ® had no role interpretation of findings, data analysis, or manuscript preparation. The authors have no affiliation with MitoQ® and were given full rights to publish all findings without approval from MitoQ®.
Author information
Authors and Affiliations
Contributions
TLM, CJM and AJRH conceived and designed the study. TLM, CJM, TP, CLM, RFD, SCB, RN, WW, TAM, AH performed the experiments and TP, TLM, CJM, AJRH analysed the data. TP, TLM, CJM and AJRH co-wrote the manuscript, and all authors approved the final manuscript version.
Corresponding author
Ethics declarations
Conflict of interest
All authors declare no competing interests.
Additional information
Communicated by Michalis G Nikolaidis.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
421_2020_4396_MOESM1_ESM.pptx
Supplementary file1 Supplementary figure 1. Quantification of mitochondrial oxidative phosphorylation complexes from western blots shown in figure 4B. (PPTX 167 kb)
Rights and permissions
About this article
Cite this article
Pham, T., MacRae, C.L., Broome, S.C. et al. MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle-aged men. Eur J Appl Physiol 120, 1657–1669 (2020). https://doi.org/10.1007/s00421-020-04396-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-020-04396-4