Acetyl-
            <scp>l</scp>
            -carnitine fed to old rats partially restores mitochondrial function and ambulatory activity

Hagen, Tory M.; Ingersoll, Russell T.; Wehr, Carol M.; Lykkesfeldt, Jens; Vinarsky, Vladimir; Bartholomew, James C.; Song, Mi Hye; Ames, Bruce N.

doi:10.1073/pnas.95.16.9562

Cited by 244 publications

(193 citation statements)

References 31 publications

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“…Evidence has been also presented that supports the conclusion that the acetylcarnitine/carnitine system buffers the CoASH/acetylCoA ratio in the mitochondrial matrix [9].…”

supporting

confidence: 50%

Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

Aureli

Puccetti

Cocco

et al. 1999

European Journal of Biochemistry

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The biochemical pathways involved in acetyl-l-carnitine utilization were investigated in conscious, freely moving rats by 13 C NMR spectroscopy. Following 4-h [(1,2-13 C 2 )acetyl]-l-carnitine infusion in fasted animals, the free carnitine levels in serum were increased, and an efflux of unlabelled acetyl-l-carnitine from tissues was observed. [(1,2-13 C 2 )Acetyl]-l-carnitine was found to enter biosynthetic pathways in liver, and the acetyl moiety was incorporated into both cholesterol and 3-hydroxybutyrate carbon skeleton. In accord with the entry of [(1,2-13 C 2 )acetyl]-l-carnitine in the mitochondrial acetylCoA pool associated with tricarboxylic acid cycle, the 13 C label was also found in liver glutamate, glutamine, and glutathione. The analysis of the 13 C-labelling pattern in 3-hydroxybutyrate and cholesterol carbon skeleton provided evidence that the acetyl-l-carnitine-derived acetylCoA pool used for ketone bodies synthesis in mitochondria was homogeneous, whereas cholesterol was synthesized from two different acetylCoA pools located in the extra-and intramitochondrial compartment, respectively. Furthermore, cholesterol molecules were shown to be preferentially synthesized by the metabolic route involving the direct channelling of CoA-activated mitochondria-derived ketone bodies into 3-hydroxy-3-methylglutarylCoA pathway, prior to equilibration of their acyl groups with extramitochondrial acetylCoA pool via acetoacetylCoA thiolase.Keywords: acetyl-l-carnitine; NMR spectroscopy; carbon-13; cholesterol; lipogenesis.Acetyl-l-carnitine is a major esterified carnitine congener in most mammalian tissues [1,2]. It is synthesized by carnitine O-acetyltransferase reaction (EC 2.3.1.7), which reversibly converts acetylCoA and free carnitine to acetyl-l-carnitine and CoASH without ATP utilization. Carnitine O-acetyltransferase activity was reported to be present almost in all tissues [3,4], and in the liver, it was found in peroxisomes, mitochondria, and microsomes [5,6].Previous investigations on acetyl-l-carnitine metabolism have focused on its role in energy-producing processes [7,8]. Evidence has been also presented that supports the conclusion that the acetylcarnitine/carnitine system buffers the CoASH/acetylCoA ratio in the mitochondrial matrix [9].To date, however, no detailed study has investigated both the role of acetyl-l-carnitine in acetyl groups trafficking between intracellular organelles and its involvement in oxidative and biosynthetic processes in vivo.As a product of peroxisomal b-oxidation, acetyl-l-carnitine may be shuttled out from peroxisomes to the cytosol [10,11], while the acetylCoA synthesized in mitochondria by glucose or fatty acid oxidation may be transported to the cytosolic compartment as acetyl-l-carnitine both in liver [12,13] and heart myocytes [14]. Studies on exogenous administration of ([1-14 C]acetyl)-l-carnitine in 24-h fasted mice reported that most acetyl moiety was oxidized in mitochondria and radioactivity was released as 14 CO 2 [15]. Moreover, the liposoluble fraction o...

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“…Evidence has been also presented that supports the conclusion that the acetylcarnitine/carnitine system buffers the CoASH/acetylCoA ratio in the mitochondrial matrix [9].…”

supporting

confidence: 50%

Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

Aureli

Puccetti

Cocco

et al. 1999

European Journal of Biochemistry

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“…One reason is that LA+ALC act on different pathways necessary for mitochondria: LA is a mitochondrial antioxidant and cofactor of pyruvate dehydrogenase, while ALC is an energy enhancer [25,41]. Another possibility is that ALC, although stimulating mitochondrial function, may cause side effects of oxidative stress in mitochondria [42], while LA, an effective mitochondrial antioxidant, is able to ameliorate that side effect of ALC. The complementary effect may also come from the different functions of LA and ALC on the four various aspects.…”

Section: Discussionmentioning

confidence: 99%

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

et al. 2007

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Aims/hypothesis The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-α-lipoic acid (LA) and acetyl-L-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes. Methods Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several transcription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO 2 production from [1-14 C] palmitate. Results Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis. Conclusions/interpretation We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism.

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“…Other necessary cofactors necessary for mitochondrial function, such as carnitine and cardiolipin, also decline with age (27,28). Carnitine loss, for example, can limit the transport of fatty acids into mitochondria for β-oxidation, which is the major source for ATP synthesis.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

et al. 2001

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Oxidative stress has been implicated as a causal factor in the aging process of the heart and other tissues. To determine the extent of age-related myocardial oxidative stress, oxidant production, antioxidant status, and oxidative DNA damage were measured in hearts of young (2 months) and old (28 months) male Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly threefold increase in the rate of oxidant production compared to young rats, as measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. Determination of myocardial antioxidant status revealed a significant twofold decline in the levels of ascorbic acid (P = 0.03), but not α-tocopherol. A significant age-related increase (P = 0.05) in steady-state levels of oxidative DNA damage was observed, as monitored by 8-oxo-2′-deoxyguanosine levels. To investigate whether dietary supplementation with (R)-α-lipoic acid (LA) was effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LA-supplemented rats exhibited a markedly lower rate of oxidant production that was no longer significantly different from that in cells from unsupplemented, young rats. Lipoic acid supplementation also restored myocardial ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the aging rat heart is under increased mitochondrial-induced oxidative stress, which is significantly attenuated by lipoic acid supplementation. Keywordsaging; cardiac myocytes; oxidative stress; lipoic acid Aging is associated with an increased incidence of cardiac arrhythmias and diastolic and systolic dysfunction, which may ultimately lead to heart failure. Heart failure alone is the leading cause of hospitalization, permanent disability, and death in persons over the age of HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript 65 (1) in the U.S. Because of the enormous suffering and health care burden that cardiac dysfunction causes, much effort has gone into understanding the mechanisms leading to agerelated myocardial decline. It has been difficult, however, to separate the effects of aging per se from those of age-associated diseases (atherosclerosis, diabetes, hypertension) on cardiac performance. Thus, the relative contribution of 'aging' to myocardial dysfunction is not well defined.Even though the mechanisms leading to alterations in cardiac performance are not well understood, there is reason to suspect increased oxidative stress to significantly contribute to myocardial dysfunction with age. It is generally agreed that isolated mitochondrial preparations from old compared to young hearts produce more reactive oxygen species (ROS), reflecting an age-related decline in coupling of electron transport to ATP production. These changes in mitochondria may lead to the reported increase in superoxide and hydrogen peroxide production in mitochondria prepared from old vs. young rats (2-4). Thus, it is conceiv...

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Acetyl- l -carnitine fed to old rats partially restores mitochondrial function and ambulatory activity

Cited by 244 publications

References 31 publications

Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

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Acetyl- l -carnitine fed to old rats partially restores mitochondrial function and ambulatory activity

Cited by 244 publications

References 31 publications

Entry of [(1,2‐13C2)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

Entry of [(1,2‐13C2)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

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Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis

Entry of [(1,2‐¹³C₂)acetyl]‐l‐carnitine in liver tricarboxylic acid cycle and lipogenesis