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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 U S A. 2002 Feb 19; 99(4):1876-81.PN

Abstract

We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CAT-binding affinity and activity, thus mimicking age-related change. Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction.

Authors+Show Affiliations

Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11854488

Citation

Liu, Jiankang, et al. "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." Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 4, 2002, pp. 1876-81.
Liu J, Killilea DW, Ames BN. 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 U S A. 2002;99(4):1876-81.
Liu, J., Killilea, D. W., & Ames, B. N. (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. Proceedings of the National Academy of Sciences of the United States of America, 99(4), 1876-81.
Liu J, Killilea DW, Ames BN. 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 U S A. 2002 Feb 19;99(4):1876-81. PubMed PMID: 11854488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Liu,Jiankang, AU - Killilea,David W, AU - Ames,Bruce N, PY - 2002/2/21/pubmed PY - 2002/3/26/medline PY - 2002/2/21/entrez SP - 1876 EP - 81 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 99 IS - 4 N2 - We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CAT-binding affinity and activity, thus mimicking age-related change. Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/11854488/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_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11854488 DB - PRIME DP - Unbound Medicine ER -