Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
29
2010

Carnitine

Drug Summary: Carnitine acts to facilitate the entry of fatty acids into the mitochondria. Once these fatty acids are in the mitochondria, they can be used to produce energy. Because inefficient energy production is believed to contribute to the progression of HD, carnitine therapy could result in increased energy production, and could possibly delay HD progression.

essential

Carnitine as an energy buffer^

The food we eat is broken down into different sub-units. Carbohydrates are broken down into simple sugars, proteins into amino acids, and fats into fatty acids. Figure J-6 shows a diagram depicting an overview of the breakdown of the food we eat.

This section will focus on the processes by which fatty acids are used to supply our body’s energy.

Fig J-6: Food Breakdown
Fig J-7: Fatty Acid Metabolism

Fatty acids must first be activated in the outer mitochondrial membrane before they can be used in the mitochondria. An enzyme called acyl-CoA synthetase is responsible for the activation of fatty acids. Once activation occurs, the fatty acids are transformed into molecules called acyl-CoA. Figure J-7 shows the reaction that takes place when fatty acids are activated.

Fig J-8: The Entry of Acyl-CoA into the Mitochondria

Long chain acyl-CoA molecules do not readily move through the mitochondrial membrane, and so a special transport chain is needed. Activated fatty acids in the form of acyl-CoA are carried across the mitochondrial membrane by carnitine. Once the acyl-CoA is in the mitochondria, carnitine is recycled back to the outer mitochondrial membrane to be reused again as an acyl-CoA transporter. Figure J-8 shows how carnitine transports the acyl-CoA molecule into the mitochondria.

Once inside the mitochondria, the acyl-CoA molecules will undergo a series of breakdown reactions collectively known as beta-oxidation. The most important end product of beta-oxidation is acetyl-CoA, a key molecule in the cell’s energy production. Acetyl-CoA can then enter the Krebs Cycle (one of the steps in energy metabolism) and lead to the production of ATP. (For more on the Krebs Cycle, click here.)

Aside from being an essential component of fatty acid metabolism, carnitine may contribute to normal cellular functioning by “stabilizing” the membrane against damage from harmful free radicals. Free radicals are by-products of energy metabolism and are reactive molecules that cause various cell damages.

As described in other chapters, impaired energy metabolism and damage by free radicals are two disease mechanisms believed to play a role in the progression of HD. Since carnitine is an acyl-Co-A transporter, scientists hypothesize that carnitine supplementation may increase metabolism efficiency by increasing the amounts of fatty acid available for processing in the mitochondria, thereby slowing HD progression. In addition, carnitine’s potential ability to decrease free radical damage also makes it a possible treatment for people with HD.

Various studies have investigated carnitine’s potential for improving conditions caused by mitochondrial dysfunction and impaired energy metabolism. In a recent (2000) clinical trial studying the potential efficacy of acetyl-L-carnitine (ALC), the active form of carnitine in the body, on slowing the rate of neurological decline in early-onset AD, treatment failed to affect the rate of decline. Research on the efficacy of ALC in treating mouse models of HD, however, have shown positive results. Below is a summary of some of the recent research done on acetyl-L-carnitine.

Research on Carnitine^

Virmani, et al. (1995) studied the effects of acetyl-L-carnitine (ALC) in cells exposed to mitochondrial toxins (poisons). Exposure to mitochondrial toxins decreases metabolism efficiency. The researchers hypothesized that if ALC truly increases metabolism efficiency, then ALC treatment to cells exposed to mitochondrial toxins will show increased metabolism efficiency compared to cells exposed to toxins that are not treated with ALC.

Nerve cells of fetal rats were exposed to various mitochondrial toxins such as FCCP, Rotenone, NaCN, and 3-NP. All these toxins act to decrease metabolism efficiency by interfering with proteins in the mitochondria that are involved in energy metabolism.

Exposure to the toxins caused an increase in lactate levels and a decrease in mitochondrial activity. The increased lactate levels indicated that exposure to toxins decreased energy metabolism.

Part of the effect of ALC may also be related to the decrease in free-radical formation from the damaged mitochondria. Experiments by other scientists have shown that ALC protected rat nerve cells from damage caused by exposure to the free radical hydrogen peroxide.

Hagen, et al. (1998) investigated the effects of ALC in aging rats. Studies have reported that there is a decline in mitochondrial energy metabolism in normal aging. Researchers believe that mitochondrial DNA, proteins, and fats are continually damaged during our lifetime, resulting in a decline in mitochondrial function as we age. Furthermore, mutations accumulated in genes that encode the proteins needed by the mitochondria could alter the components of the electron transport chain, leading to inefficient electron transport. Inefficient electron transport is known to cause an increase in the production of free radicals, which causes further damage to the cell. Thus, mitochondrial dysfunction is speculated to be a contributing factor of the aging process.

Carnitine levels have also been found to decrease with age, depriving mitochondria of fatty acids for oxidation. The researchers found that treatment of aging rats with ALC increased cellular respiration and reversed the age-associated decline of certain molecules that contribute to the maintenance of the structure and function of the mitochondrial membrane.

Furthermore, ALC treatment improved the motor abilities of both young and old rats. ALC supplementation significantly restored overall activity levels in old animals, suggesting that decline in activity may be the result of mitochondrial damage. However, while ALC increased energy metabolism, it also led to an increase in the production of free radicals. This may indicate that while ALC can increase the supply of energy in cells, it cannot mask the age-associated loss of efficiency in the electron-transport chain. Long-term administration of ALC to animals must be done to determine whether it may improve mitochondrial dysfunction that occurs during the aging process and in pathological conditions such as HD.

Thal, et al. (2000) A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Two hundred twenty nine Alzheimer’s Disease patients ages 45 – 65 were enrolled in the study. They were treated with ALC (1 g tid) or placebo. Primary outcome measures were the Alzheimer’s Disease Assessment Scale-Cognitive Component and the Clinical Dementia Rating Scale.

Two-hundred twenty-nine patients were enrolled and randomized to drug treatment, with 117 taking placebo and 112 taking ALC. There were no significant differences between the two groups at baseline. For the primary outcome measures, there were no significant differences between the treatment groups on the change from baseline to endpoint in the intent-to-treat analysis. There were no significant differences in the incidence of adverse events resulting from treatment.

Overall, in a prospectively performed study in young-onset AD patients, ALC failed to slow decline. Less decline was seen on the MMSE in the completer sample only, with the difference being mediated by reducing decline in attention.

Vamos et al. (2010): A study of HD mice found that high doses of carnitine (45 mg/kg every day) caused improvements in HD mice. The treated HD mice lived 14.9% longer than untreated HD mice, and had improvements in motor activity: they moved more, and were faster. Furthermore, when the researchers performing the study looked at the brains of the treated HD mice, they found fewer neuronal inclusions, the clumps of mutant huntingtin. This suggests that carnitine is neuroprotective in HD mice, and might help treat HD.

For further reading^

  1. Virmani, et al. “Protective action of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors.” Pharmacological Research. 1995; 32: 383-89.
    This article reports that carnitine can improve energy production initially inhibited by various toxins.
  2. Hagen, et al. “Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity.” Proc. Natl. Acad Sci USA 1998; 95: 9562-66.
    This article reports that carnitine treatment can lead to beneficial effects in aging rats.
  3. Thal, et al. “A 1-year controlled trial of acetyl-l-carnitine in early-onset AD.” Neurology. 2000 Sep 26;55(6):805-10
  4. For information on uncouplers and inhibitors, visit http://www.bmb.leeds.ac.uk/illingworth/oxphos/poisons.htm
    This page contains information on various mitochondrial toxins.
  5. For information on fatty acid oxidation, visit http://web.indstate.edu/thcme/mwking/fatty-acid-oxidation.html
    This page contains detailed, comprehensive information on fatty acid metabolism. Includes figures, structures of various lipid molecules, etc. Link to this page to learn more about carnitine, beta-oxidation, and how fats are used in our body.
  6. http://www.degussa-health-nutrition.com/degussa/html/e/health/eng/kh/l3.1.htm
    This page contains a good overview of fatty acids and fatty acid oxidation.
  7. Vamos E, Voros K, Vecsei L, Klivenyi P. Neuroprotective effects of L-carnitine in a transgenic animal model of Huntington’s disease. Biomed Pharmacother. 2010 Apr;64(4):282-6. Epub 2009 Oct 27. This technical paper describes the study of carnitine supplementation in HD mice.

-E. Tan, 9-22-01; Updated by P. Chang, 5-6-03, Updated by M. Hedlin 8-5-11