The "rejuvenatory" impact of lipoic acid on mitochondrial function in aging rats may reflect induction and activation of PPAR-gamma coactivator-1alpha.

In aging rats, lipoic acid exerts a "rejuvenative" impact on mitochondria in various tissues, boosting mitochondrial membrane potential and oxygen consumption, while decreasing mitochondrial production of oxidants. A likely explanation for this phenomenon is that the mitochondria in aging rodents are structurally and functionally impaired by excessive oxidant stress - and that lipoic acid reverses this damage by amplifying key antioxidant mechanisms that protect mitochondria. A likely mediator of this effect is PPARgamma coactivator-1alpha (PGC-1alpha), which recently has been shown to promote transcription of the manganese-dependent superoxide dismutase, uncoupling protein-2, and an array of other proteins which provide antioxidant protection to mitochondria. Lipoic acid has been reported to activate both p38 MAP kinase and AMP-activated kinase (AMPK); p38 MAP kinase can boost the transcription, half-life, and coactivational activity of PGC-1alpha, and AMPK is known to promote its transcription in skeletal muscle and endothelial cells. Thus, it is intriguing to speculate that the remarkable antioxidant effects of lipoic acid therapy reflect not only induction of phase 2 antioxidants (e.g. glutathione and heme oxygenase-1), but also induction of various proteins that function expressly to protect mitochondria from self-generated oxidant stress. Further research is required to evaluate this model.