Mitochondrial activity progressively declines during ageing and in many neurodegenerative diseases. Caloric restriction (CR) has been suggested as a dietary intervention that is able to postpone the detrimental aspects of aging as it ameliorates mitochondrial performance. This effect is partially due to increased mitochondrial biogenesis. The nutrient-sensing PGC-1 is a transcriptional coactivator that promotes the expression of mitochondrial genes and is induced by CR. It is believed that many of the mitochondrial and metabolic benefits of CR are due to increased PGC-1 activity. The increase of PGC-1 is also positively linked to neuroprotection and its decrement has been involved in the pathogenesis of many neurodegenerative diseases. This paper aims to summarize the current knowledge about the role of PGC-1 in neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1 -governed pathways could be used as target for nutritional intervention to prevent neurodegeneration. 1. Introduction Mitochondria are dynamic organelles fundamental for cell life. The central roles of mitochondria in metabolism place them at the center stage of global energy modulation. Indeed, these organelles are best known for producing ATP via oxidative phosphorylation (OXPHOS). In the matrix, tricarboxylic acid cycle (TCA) generates reduced carriers (NADH and FADH2), which donate electrons to the inner membrane-localized electron transport chain (ETC). In this way electrons derived from metabolites flow through the ETC generating intermembrane proton gradient (mitochondrial membrane potential), which fundamental for the activity of rotary turbine-like ATP synthase producing ATP from ADP [1]. Mitochondria contain a circular genome, mitochondrial DNA (mtDNA), which has been reduced during evolution through gene transfer to the nucleus. Even if mitochondria are characterized by an own genome encoding for 13 subunits of ETC, they strongly necessitate of many other nuclear encoded proteins (about 1000–1500) for the execution of their function [2]. Therefore, it is clear that mitochondria are not autonomous entities but strongly dependent on nuclear genome. Indeed, mitochondrial homeostasis is assured by a well-functioning bidirectional network of mitochondrial-nuclear communications (MN-C). MN-C control many cell activities including mitochondrial biogenesis, an intricate biological process consisting in the growth and division of preexisting mitochondria that requires the replication of the mtDNA and the synthesis and
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