Abstract
Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.
Highlights
PGC-1α’s Roles in the Regulation of Gene Expression in Peripheral TissuesPGC-1α was first discovered as an interacting factor of PPARγ and the thyroid hormone receptor in adipose tissue, with its expression causing an increase in mitochondrial mass and respiration and the up-regulation nuclear-encoded mitochondrial transcripts such as uncoupling protein 1 (Ucp1) [40]
Introduction published maps and institutional affilMany studies implicate mitochondrial dysfunction as a key contributor to neuronal dysfunction in disease states
Mitochondrial dysfunction can arise by different routes, such as mutations in genes implicated in mitochondrial clearance and function, oxidative stress induced by environmental toxins, disruption of transcriptional programs for mitochondrial function, and reduction of cellular activity associated with hypoxia and/or hypometabolism
Summary
PGC-1α was first discovered as an interacting factor of PPARγ and the thyroid hormone receptor in adipose tissue, with its expression causing an increase in mitochondrial mass and respiration and the up-regulation nuclear-encoded mitochondrial transcripts such as uncoupling protein 1 (Ucp1) [40]. PGC-1α expression is robustly induced following exercise in both rodents and humans [14,19,24], where it confers an oxidative phenotype to fast-twitch, glycolytic fiber-types [41] and enhances glucose as a source of ATP by regulating Glut4 [42]. PGC-1α-dependent transcription leads to a metabolic shift from glucose utilization to glycogenolysis, gluconeogenesis, fatty acid oxidation, ketone body utilization and bile acid homeostasis. Many of these programs are regulated by the interaction of PGC-1α with a number of liver-enriched transcription factors [24]. While mitochondria in PGC-1α null hepatocytes exhibit no obvious changes in number or morphology, oxygen consumption is significantly reduced [46]
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