PGC1 transcriptional co-activators are important regulators of mitochondrial biogenesis and respiration. Two new studies from the Spiegelman laboratory now shed light on the role of PGC1 in several disease aetiologies. PGC1α and PGC1β are implicated in oxidative-damage-related neurodegeneration by suppressing the generation of reactive oxygen species (ROS). Moreover, PGC1α is associated with defective energy homeostasis associated with Leigh syndrome French Canadian variant (LSFC), a genetic disorder that is characterized by neurodegeneration and severe liver defects.

Given that the mitochondrial electron-transport chain is the main producer of ROS, the authors examined the role of PGC1α and PGC1β in ROS metabolism. Following exposure to oxidative stress, the expression levels of Pgc1α, and to a lesser extent Pgc1β, were increased, as were those of several genes encoding components of the ROS defence system including several ROS-detoxifying enzymes. RNA-interference-mediated knockdown of either one or both co-activators reduced the basal gene-expression levels of components of the ROS defence system, and the induction of gene expression following an oxidative challenge was practically abolished. Cells from Pgc1α-null mice showed reduced gene expression of components of the ROS defence system and increased sensitivity to oxidative stress. Spiegelman and co-workers therefore concluded that PGC1α and PGC1β regulate the basal and induced gene-expression levels of the ROS defence system.

By challenging the brain of Pgc1α-knockout mice with oxidative stress, Spiegelman and colleagues observed increased neuronal damage, which occurred with excessive oxidative stress. By contrast, overexpression of PGC1α in neuronal cells that were subsequently exposed to oxidative stress resulted in increased survival. This protective effect was associated with increased gene expression of ROS-detoxifying enzymes.

These findings imply that PGC1α “may serve as an adaptive set-point regulator” that allows the stimulation of mitochondrial electron transport without causing self-inflicted oxidative damage. In other words, PGC1α can turn up the heat safely.

In a second study, the Spiegelman group purified the PGC1α holoenzyme complex and identified the LRP130 protein, which is mutated in patients with LSFC, as one its components. The authors showed that LRP130 regulates the transcription of the Pgc1α gene, which, in turn, regulates many genes. They found that LRP130 is required for the regulation of certain PGC1α target genes that are required for gluconeogenesis and mitochondrial electron transport. The significance of these findings was tested in vivo by treating mice with Lrp130 small interfering RNA, and the mice were subsequently either fed or starved. The expression of several gluconeogenesis genes was strongly induced in control mice that had been starved, but this induction was blocked in Lrp130-knockdown mice. Glucose and ATP production were also significantly reduced in these mice compared with control mice. Together, these data link LRP130 and PGC1α to defective hepatic glucose and energy homeostasis in patients with LSFC. Whether the neurodegeneration phenotype of LSFC is linked to a sensitivity to oxidative stress remains to be determined.