Neuron-Specific Mechanisms Control the Mitochondrial Regulator PGC-1a. (17th December 2021) - McGregor, Eric
Abstract: Mitochondrial dysfunction has been proposed as a hallmark of the aging process. Specifically, as a function of aging, mitochondria appear to have decreased enzyme activity and respiratory capacity and increase reactive oxygen species production. Brain aging is associated with morphological and homeostatic changes, including alterations in brain size, cognitive impairment, and white and grey matter integrity. However, the causes of these changes remain an open and actively pursued field of study. The ubiquitously expressed transcriptional coactivator peroxisome proliferator-activated receptor gamma-coactivator 1 (PGC-1a) has been described as the master regulator of mitochondrial function. Despite the emerging connections between PGC-1a and disease vulnerability, the regulation of PGC-1a outside of the skeletal muscle, liver, and adipose tissue is not well defined. This is particularly true in the brain, where PGC-1a is enriched in neurons, and alterations in expression levels have been linked to neurodegenerative disorders. Here we report that astrocytes and neurons differ substantially in mitochondrial status and the transcript variants of PGC-1a expressed, including using a neuron-specific promoter. Taking advantage of the ability of the tau-kinase GSK-3b to influence PGC-1a expression, we investigate how transcript variants are differentially regulated in primary neurons and astrocytes. Neuronal PGC-1a responds robustly to GSK3b inhibition by lithium, switching the dominant promoter, leading to changes in isoform distribution and abundance, while astrocytes are refractory to lithium treatment. The data presented here highlight key mechanisms for neuron-specific metabolic regulation that are likely to be relevant to neurodegenerative diseases that have a link to mitochondrial dysfunction.