ABSTRACT
Introduction...................................................................................................... 293 Redox Status of Cells and the Extracellular Environment .............................. 296 Cellular Redox Status .................................................................................. 297 Extracellular Redox Status........................................................................... 299
Effect of Lipoic Acid on Cellular and Extracellular Redox Status ................. 300 Lipoic Acid Transport into Cells and Perturbation of the Cellular Redox Status ............................................................................................ 300
Lipoic Acid Reduction to DHLA and Redox Changes Caused by DHLA ................................................................................................. 301
DHLA Release into the Extracellular Cellular Environment and Consequent Redox Changes .................................................................... 302
Overview of Lipoic Acid Redox Cycling in Cells .......................................... 306 Modulation of Cellular Energy Status by Lipoic Acid ................................... 307 Lipoic Acid and Mitochondrial Functionality ................................................. 307 Perspective ....................................................................................................... 308 Abbreviations ................................................................................................... 309 References ........................................................................................................ 309
Lipoic acid (LA) has recently gained substantial attention as a therapeutic agent and nutritional supplement (Packer et al., 2001; Ames and Liu, 2004; Smith et al., 2004). Exogenous LA supplementation has been reported to decrease ischemiareperfusion injury in peripheral nerves (Mitsui et al., 1999), brain (Cao and Phillis, 1995), and liver (Muller et al., 2003; Dulundu et al., 2007), and has been shown to be beneficial in the treatment of disorders such as polyneuropathy and diabetes (Bustamante et al., 1998; Packer et al., 2001). In cell culture studies,
LA supplementation has been demonstrated to modulate NF-kB signaling (Suzuki et al., 1992), MAPK signaling (Cho et al., 2003b), phosphoinositide 3-kinase (PI3K)=protein kinase B (Akt) signaling (Muller et al., 2003; Zhang et al., 2007), inhibit tyrosine phosphatase activity (Cho et al., 2003a), inhibit HIV replication (Baur et al., 1991), increase cellular glutathione (GSH) levels (Han et al., 1995b; Han et al., 1997a) as well as promote glucose uptake (Roy et al., 1997; Khanna et al., 1999). The mechanism by which LA can modulate so many activities in cells has not been completely characterized due to the complex chemistry of LA. Structurally, LA is a very unique compound containing (1) a medium length fatty acid tail and (2) a thiolane ring that provides antioxidant functions as well as undergoes redox changes similar to GSH (Figure 12.1). The thiolane ring of LA can be reduced to vicinal thiols (dihydrolipoic acid [DHLA]) in cells utilizing NADH and NADPH reducing equivalents (Handelman et al., 1994; Haramaki et al., 1997). The biological effects of LA may be mainly attributed to LA’s (1) antioxidant capacity, (2) fatty acid properties, and (3) redox chemistry.
