Advertisement

Neurochemical Research

, Volume 34, Issue 4, pp 755–763 | Cite as

Mitochondrial Decay in the Brains of Old Rats: Ameliorating Effect of Alpha-Lipoic Acid and Acetyl-l-carnitine

  • Jiangang Long
  • Feng Gao
  • Liqi Tong
  • Carl W. Cotman
  • Bruce N. Ames
  • Jiankang Liu
Original Paper

Abstract

To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-α-lipoic acid plus acetyl-l-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly decreased endogenous antioxidants and superoxide dismutase activity; more oxidative damage to lipids and proteins; and decreased activities of complex I, IV and V. Complex I showed a decrease in binding affinity (increase in Km) for substrates. Feeding LA/ALC to old rats partially restored age-associated mitochondrial dysfunction to the levels of the young rats. These results indicate that oxidative mitochondrial decay plays an important role in brain aging and that a combination of nutrients targeting mitochondria, such as LA/ALC, could ameliorate mitochondrial decay through preventing mitochondrial oxidative damage.

Keywords

Binding affinity (KmBrain mitochondria Mitochondrial complex activity Enzyme kinetics Oxidative damage 

Notes

Acknowledgements

The authors thank Dr. Afshin Gharib for taking care of the animals. This work was supported by the Ellison Medical Foundation Grants S-0422-99, the National Institute on Aging AG17140, and the National Center for Complementary and Alternative Medicine Research Scientist Award K05 AT001323-4 (B. N. A.), and National Institutes of Health grants NEI EY016101, NIA AG023265, and NCCAM AT01918 (B. N. A. and J. L.) and NIA AG012694 (C. W. C).

References

  1. 1.
    Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495. doi: 10.1016/j.cell.2005.02.001 PubMedCrossRefGoogle Scholar
  2. 2.
    Judge S, Jang YM, Smith A, Hagen T, Leeuwenburgh C (2005) Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J 19:419–421PubMedGoogle Scholar
  3. 3.
    Leine RL, Garland D, Oliver CN et al (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478. doi: 10.1016/0076-6879(90)86141-H CrossRefGoogle Scholar
  4. 4.
    Ames BN, Suh JH, Liu J (2006) Enzymes lose binding affinity for coenzymes and substrates with age: a strategy for remediation. In: Kaput J (ed) Nutrigenomics: concepts and technologies. Wiley, Hoboken, pp 277–291Google Scholar
  5. 5.
    Naarro A, Boveris A (2004) Rat brain and lier mitochondria develop oxidative stress and lose enzymatic activities on aging. Am J Physiol Regul Integr Comp Physiol 287(5):R1244–R1249. doi: 10.1152/ajpregu.00226.2004 Google Scholar
  6. 6.
    Feuers RJ (1998) The effects of dietary restriction on mitochondrial dysfunction in aging. Ann NY Acad Sci 854:192–201. doi: 10.1111/j.1749-6632.1998.tb09902.x PubMedCrossRefGoogle Scholar
  7. 7.
    Liu J, Head E, Gharib AM et al (2002) Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:2356–2361. doi: 10.1073/pnas.261709299 PubMedCrossRefGoogle Scholar
  8. 8.
    Liu J, Killilea DW, Ames BN (2002) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:1876–1881. doi: 10.1073/pnas.261709098 PubMedCrossRefGoogle Scholar
  9. 9.
    Packer L, Witt EH, Tritschler HJ (1995) Alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med 19:227–250. doi: 10.1016/0891-5849(95)00017-R PubMedCrossRefGoogle Scholar
  10. 10.
    Suh JH, Shenvi SV, Dixon BM et al (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci USA 101:3381–3386. doi: 10.1073/pnas.0400282101 PubMedCrossRefGoogle Scholar
  11. 11.
    Hagen TM, Ingersoll RT, Wehr CM et al (1998) Acetyl-l-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci USA 95:9562–9566. doi: 10.1073/pnas.95.16.9562 PubMedCrossRefGoogle Scholar
  12. 12.
    Alie G, Liu J, Shenk JC et al (2008) Neuronal mitochondrial amelioration by feeding acetyl-l-carnitine and lipoic acid to aged rats. J Cell Mol Med [epub ahead of print]. doi: 10.1111/j.1582-4934.2008.00324.x
  13. 13.
    Milgram NW, Araujo JA, Hagen TM, Treadwell B, Ames BN (2007) Acetyl-l-carnitine and alpha-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests. FASEB J 21:3756–3762. doi: 10.1096/fj.07-8531com PubMedCrossRefGoogle Scholar
  14. 14.
    Montgomery SA, Thal LJ, Amrein R (2003) Meta-analysis of double blind randomized controlled clinical trials of acetyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 18:61–71. doi: 10.1097/00004850-200303000-00001 PubMedCrossRefGoogle Scholar
  15. 15.
    Ziegler D, Luft D (2002) Clinical trials for drugs against diabetic neuropathy: can we combine scientific needs with clinical practicalities? Int Rev Neurobiol 50:431–463PubMedCrossRefGoogle Scholar
  16. 16.
    McMackin CJ, Widlansky ME, Hamburg NM et al (2007) Effect of combined treatment with alpha-Lipoic acid and acetyl-l-carnitine on vascular function and blood pressure in patients with coronary artery disease. J Clin Hypertens (Greenwich) 9:249–255Google Scholar
  17. 17.
    Ames BN, Elson-Schwab I, Siler EA (2002) High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr 75:616–658PubMedGoogle Scholar
  18. 18.
    Liu J (2008) The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res 33:194–203. doi: 10.1007/s11064-007-9403-0 PubMedCrossRefGoogle Scholar
  19. 19.
    Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26:5256–5264. doi: 10.1523/JNEUROSCI.0984-06.2006 PubMedCrossRefGoogle Scholar
  20. 20.
    Lenaz G, Fato R, Baracca A, Genoa ML (2004) Mitochondrial quinone reductases: complex I. Methods Enzymol 382:3–20. doi: 10.1016/S0076-6879(04)82001-9 PubMedCrossRefGoogle Scholar
  21. 21.
    Sun L, Luo C, Long J, Wei D, Liu J (2006) Acrolein is a mitochondrial toxin: effects on respiratory function and enzyme activities in isolated rat liver mitochondria. Mitochondrion 6:136–142. doi: 10.1016/j.mito.2006.04.003 PubMedCrossRefGoogle Scholar
  22. 22.
    Yarian CS, Rebrin I, Sohal RS (2005) Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria. Biochem Biophys Res Commun 330:151–156. doi: 10.1016/j.bbrc.2005.02.135 PubMedCrossRefGoogle Scholar
  23. 23.
    Smigrodzki R, Parks J, Parker WD (2004) High frequency of mitochondrial complex I mutations in Parkinson’s disease and aging. Neurobiol Aging 25:1273–1281. doi: 10.1016/j.neurobiolaging.2004.02.020 PubMedCrossRefGoogle Scholar
  24. 24.
    Yoon YS, Lee JH, Hwang SC, Choi KS, Yoon G (2005) TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex I activity with senescent arrest in M1Lu cells. Oncogene 24:1895–1903. doi: 10.1038/sj.onc.1208262 PubMedCrossRefGoogle Scholar
  25. 25.
    Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004) Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94:53–59. doi: 10.1161/01.RES.0000109416.56608.64 PubMedCrossRefGoogle Scholar
  26. 26.
    Liu J, Yeo HC, Doniger SJ, Ames BN (1997) Assay of aldehydes from lipid peroxidation: gas chromatography-mass spectrometry compared to thiobarbituric acid. Anal Biochem 245:161–166. doi: 10.1006/abio.1996.9990 PubMedCrossRefGoogle Scholar
  27. 27.
    Long J, Wang X, Gao H et al (2006) Malonaldehyde acts as a mitochondrial toxin: inhibitory effects on respiratory function and enzyme activities in isolated rat liver mitochondria. Life Sci 79:1466–1472. doi: 10.1016/j.lfs.2006.04.024 PubMedCrossRefGoogle Scholar
  28. 28.
    Volobouea LA, Liu J, Suh JH, Ames BN, Miller SS (2005) (R)-alpha-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci 46:4302–4310. doi: 10.1167/ios.04-1098 CrossRefGoogle Scholar
  29. 29.
    Packer L, Tritschler HJ, Wessel K (1997) Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 22:359–378. doi: 10.1016/S0891-5849(96)00269-9 PubMedCrossRefGoogle Scholar
  30. 30.
    Calabrese , Ravagna A, Colombrita C et al (2005) Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2. J Neurosci Res 79:509–521. doi: 10.1002/jnr.20386 PubMedCrossRefGoogle Scholar
  31. 31.
    Liu J, Atamna H, Kuratsune H, Ames BN (2002) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann NY Acad Sci 959:133–166PubMedGoogle Scholar
  32. 32.
    Calo LA, Pagnin E, Davis PA et al (2006) Antioxidant effect of l-carnitine and its short chain esters: relevance for the protection from oxidative stress related cardiovascular damage. Int J Cardiol 107:54–60. doi: 10.1016/j.ijcard.2005.02.053 PubMedCrossRefGoogle Scholar
  33. 33.
    Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-l-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med 42:371–384. doi: 10.1016/j.freeradbiomed.2006.11.006 PubMedCrossRefGoogle Scholar
  34. 34.
    Shen W, Liu K, Tian C et al (2008) R-alpha-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes. Diabetologia 51:165–174. doi: 10.1007/s00125-007-0852-4 PubMedCrossRefGoogle Scholar
  35. 35.
    Shen W, Liu K, Tian C et al (2008) Protective effects of R-alpha-lipoic acid and acetyl-l-carnitine in MIN6 and isolated rat islet cells chronically exposed to oleic acid. J Cell Biochem 104:1232–1243. doi: 10.1002/jcb.21701 Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jiangang Long
    • 1
    • 2
  • Feng Gao
    • 2
  • Liqi Tong
    • 1
  • Carl W. Cotman
    • 1
  • Bruce N. Ames
    • 2
  • Jiankang Liu
    • 1
    • 3
  1. 1.Institute for Brain Aging and DementiaUniversity of CaliforniaIrvineUSA
  2. 2.Children’s Hospital Oakland Research InstituteOaklandUSA
  3. 3.Graduate Center for ToxicologyUniversity of Kentucky College of MedicineLexingtonUSA

Personalised recommendations