Lesson 38: Alpha-lipoic acid Copy

Alpha-lipoic acid is used in the body to break down carbohydrates and to make energy for the other organs in the body. Alpha-lipoic acid seems to work as an antioxidant, which means that it might provide protection to the brain under conditions of damage or injury. Alpha lipoic acid (ALA) is naturally produced in the human body in very small amounts, but is also available in some foods such as spinach and broccoli. ALA is unique in that it can function in both water and fat environments.* ALA promotes the production of glutathione and can also recycle vitamins C and E, thereby enhancing their antioxidant activities.* In addition, ALA may help to maintain healthy neural tissues, promote proper glucose metabolism and support healthy cardiovascular function.

Researchers have discovered a possible explanation for the surprisingly large range of biological effects that are linked to a micronutrient called lipoic acid: It appears to reset and synchronize circadian rhythms, or the “biological clock” found in most life forms. The ability of lipoic acid to help restore a more normal circadian rhythm to aging animals could explain its apparent value in so many important biological functions, ranging from stress resistance to cardiac function, hormonal balance, muscle performance, glucose metabolism and the aging process. The findings were made by biochemists from the Linus Pauling Institute at Oregon State University, and published in Biochemical and Biophysical Research Communications, a professional journal. The research was supported by the National Institutes of Health, through the National Center for Complementary and Alternative Medicine.

Lipoic acid has been the focus in recent years of increasing research by scientists around the world, who continue to find previously unknown effects of this micronutrient. As an antioxidant and compound essential for aerobic metabolism, it’s found at higher levels in leafy vegetables such as spinach and broccoli.

“This could be a breakthrough in our understanding of why lipoic acid is so important and how it functions,” said Tory Hagen, the Helen P. Rumbel Professor for Healthy Aging Research in the Linus Pauling Institute, and a professor of biochemistry and biophysics in the OSU College of Science.

“Circadian rhythms are day-night cycles that affect the daily ebb and flow of critical biological processes,” Hagen said. “The more we improve our understanding of them, the more we find them involved in so many aspects of life.”

Almost one-third of all genes are influenced by circadian rhythms, and when out of balance they can play roles in cancer, heart disease, inflammation, hormonal imbalance and many other areas, the OSU researchers said.Of particular importance is the dysfunction of circadian rhythms with age. In elderly humans, it’s well-known that circadian rhythms break down and certain enzymes don’t function as efficiently, or as well as they should, said Dove Keith, a research associate in the Linus Pauling Institute and lead author on this study. If lipoic acid offers a way to help synchronize and restore circadian rhythms, it could be quite significant. In this case the scientists studied the “circadian clock” of the liver. Lipid metabolism by the liver is relevant to normal energy use, metabolism, and when dysfunctional can help contribute to the “metabolic syndrome” that puts millions of people at higher risk of heart disease, diabetes and cancer.


Recent experimental research shows alpha-lipoic acid (ALA) may have new protein targets within the mitochondria that are crucial for energy supply. The newly discovered mechanism suggests ALA supplementation to be an effective strategy for mitochondrial function in chronic inflammatory states. ALA has diverse antioxidant and anti-inflammatory functions. It is also a cofactor for key mitochondrial enzymes involved in glucose metabolism and energy production, and may be essential for energy metabolism. Previous research showed that ALA supplementation increased mitochondrial capacity, partially restored mitochondrial enzyme activity and increased ATP production, when in the presence of inflammatory induced nitrous oxide (NO). Other research also shows small molecular S-nitosothiols, which act as reservoirs and donors for NO, down-regulate mitochondrial function.
NO is a soluble and highly diffusible gas generated by a wide variety of cells and required for endothelium-derived smooth muscle relaxation. NO regulates protein function through a process called S-nitrosylation and it is believed this process is important for key metabolic pathways. However, excess NO, produced in inflammatory states, is toxic to cells and, when unregulated, increases reactive nitrogen species (RNS) causing nitrosative stress. This type of stress can affect cell function and increase the potential of pathological processes, especially in endothelial cells, and may diminish oxidative phosphorylation and mitochondrial energy production. Due to the previous findings, researchers decided to test the theory that diminished mitochondrial enzyme function central to energy production, due to nitrosative stress, can be alleviated with ALA supplementation through S-nitrosylation regulation. The results showed NO adversely affected the function of a complex III enzyme in the electron transport chain and a subunit of alpha-ketoglutarate dehydrogenase complex (KDC), an important enzyme in the Krebs cycle. When ALA was introduced, it significantly reduced S-nitrosylation in both of these mitochondrial enzyme complexes and effectively restored mitochondrial enzyme activities inhibited by excess NO, while significantly increasing ATP production. 

The regulatory functions of ALA may now include altering protein S-nitrosylation and regulating the expression of some proteins affected by S-nitrosylation mechanisms. Glutathione (GSH) levels were also analysed and it is proposed that this new mechanism of ALA may be through the regulation of GSH, as this antioxidant protects mitochondrial complexes from NO-induced damage. The researchers concluded that the studies shed light on a new mechanism of antioxidant activity of ALA and suggest a strategy for the treatment of diseases in which chronic inflammation is involved. This is particularly important for conditions such as atherosclerosis and type 2 diabetes. 


  1. Hiller S, DeKroon R, Hamlett ED, et al. Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochimica et Biophysica Acta 2016;1860(1 Pt A):36-45. [Abstract
  2. Richardson G, Benjamin N. Potential therapeutic uses for s-nitrosothiols. Clin Sci (Lond) 2002;102(1):99-105. [Abstract]