The AMPK-PGC-1α signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury

Neurons are highly sensitive to metabolic and oxidative injury, but endogenous astrocyte mechanisms have a critical capacity to provide protection from these stresses. We previously reported that the master regulator PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) is necessary for retinal astrocytes to mount effective injury responses, with particular regard to oxidative stress. Yet, this pathway has not been well studied in glia. PGC-1 alpha is a transcriptional co-activator that is dysregulated in a variety of neurodegenerative diseases. It functions as a master regulator of cellular bioenergetics, with the ability to regulate tissue specific responses. A key inducer of PGC-1 alpha signaling is adenosine monophosphate-activated kinase (AMPK). Thus, the AMPK-PGC-1 alpha signaling axis coordinates metabolic and oxidative damage responses in the central nervous system (CNS). Here we report that AMPK selectively regulates expression of GCLM (glutamate cysteine ligase modulatory subunit) in astrocytes, but not neurons, through PGC-1 alpha activation. Glutamate cysteine ligase (GCL) is the rate limiting enzyme in the biosynthesis of glutathione (GSH); a critical antioxidant and detoxifying peptide in the CNS. Through this mechanism we describe PGC-1 alpha-dependent induction of GSH synthesis and antioxidant activity in astrocytes, and in the rodent retina in vivo. Furthermore, we demonstrate that therapeutic agonism of this pathway with the AMP mimetic, AICAR, rescues GSH levels in vivo, while reducing RGC death and astrocyte reactivity, following retinal ischemia/reperfusion injury. This mechanism presents a novel strategy for enhancing protective astrocyte antioxidant capacity in the CNS.