Stimulation of Ca2+ release from rat liver mitochondria by the dithiol reagent alpha-lipoic acid

Rat liver mitochondria contain a Ca(2+)-specific release pathway stimulated by Ca(2+)-dependent hydrolysis of oxidized intramitochondrial pyridine nucleotides to ADP ribose and nicotinamide. We have previously shown that NAD+ hydrolysis and subsequent Ca2+ release are inhibited by cyclosporine A and that they are only possible when some critical thiols are cross-linked or oxidized, e.g. by phenylarsine oxide, gliotoxin, or peroxynitrite. We now report that the antioxidant alpha-lipoic acid stimulates Ca2+ release from intact mitochondria, i.e. with preservation of the mitochondrial membrane potential and without large-amplitude swelling. The release stimulated by alpha-lipoic acid is inhibited by cyclosporine A and is more effective when the pyridine nucleotides are oxidized. The results strongly suggest that alpha-lipoic acid stimulates the Ca(2+)-specific release pathway from intact mitochondria by oxidizing some vicinal thiols, thereby stimulating hydrolysis of oxidized pyridine nucleotides. These observations further corroborate that intact rat liver mitochondria contain a specific Ca2+ release pathway stimulated by modification of vicinal thiols. Prolonged stimulation of Ca2+ release by lipoic acid followed by its re-uptake (Ca2+ "cycling") may contribute to the detrimental, prooxidant-like effects seen with higher concentrations of lipoic acid.