The transcriptional co-activator PGC-1␣ and the NAD ؉ -dependent deacetylase SIRT1 are considered important inducers of mitochondrial biogenesis because in the nucleus they regulate transcription of nucleus-encoded mitochondrial genes. We demonstrate that PGC-1␣ and SIRT1 are also present inside mitochondria and are in close proximity to mtDNA. The mitochondrial proteome includes ϳ1500 proteins among which only 13 are expressed by the mitochondrial genome (1). Accordingly, abundance, morphology, and functional properties of mitochondria are finely controlled at the nuclear genome, where an interconnected network of transcription factors regulates the expression of mitochondrial proteins, including those that control replication and transcription of the mitochondrial genome. The same transcriptional network senses alterations of energetic homeostasis of the cells and is able to adapt mitochondrial function and biogenesis in response to nutrient availability and energy demand (2, 3).In the last few years, the NAD ϩ -dependent protein deacetylase sirtuin 1 (SIRT1) is emerging as a crucial regulator of mitochondrial biogenesis (4). Mammalian SIRT1 is homologous to the yeast silent information regulator 2 (Sir2) and belongs to class III histone deacetylates (HDACIII) that include other sirtuins (SIRT2-7) with specific subcellular localization and protein substrates. The dependence of SIRT1 on NAD ϩ links its enzymatic activity directly to the energy status of the cell, thus being activated in conditions of nutrient deprivation such as fasting and caloric restriction (5). Besides its role in modification of chromatin and silencing of transcription, by heterochromatin formation through histones modification, SIRT1 targets a wide range of transcriptional factors, including protein 53 (p53) and forkhead box O (FoxO) (6, 7). However, by regulating peroxisome proliferator-activated receptor ␥ co-activator 1␣ (PGC-1␣), through a functional protein-protein interaction, SIRT1 influences the activity of one of the most versatile metabolic transcriptional co-activators of genes involved in energy metabolism (5,8,9). In particular, PGC-1␣ represents an upstream inducer of genes of mitochondrial metabolism by positively affecting the activity of some hormone nuclear receptors (peroxisome proliferator-activated receptor ␥ and estrogen-related receptor ␣) and nuclear transcription factors (NRF-1,2) (10). NRF-1 is a downstream effector of SIRT1/PGC-1␣ and activates the expression of OxPhos components, mitochondrial transporters, and ribosomal proteins. Additionally, NRF-1 regulates the activation of the Tfam, Tfb1m, and Tfb2m promoters and indirectly affects the expression of Cox genes, Glut4 and PGC-1␣ itself (1). Importantly, the coordination of the two genomes seems to be exclusively achieved by the nucleus-encoded proteins TFAM, 2 TFB1M, and TFB2M, among which the mitochondrial transcription factor A seems to play a central role being essential for transcription, replication, and maintenance of mtDNA (11,12). mtDNA is packaged i...

Aims: The transcriptional coactivator peroxisome proliferator-activated receptor-c coactivator-1 a (PPARGC1A or PGC-1a) is a powerful controller of cell metabolism and assures the balance between the production and the scavenging of pro-oxidant molecules by coordinating mitochondrial biogenesis and the expression of antioxidants. However, even though a huge amount of data referring to the role of PGC-1a is available, the molecular mechanisms of its regulation at the transcriptional level are not completely understood. In the present report, we aim at characterizing whether the decrease of antioxidant glutathione (GSH) modulates PGC-1a expression and its downstream metabolic pathways. Results: We found that upon GSH shortage, induced either by its chemical depletion or by metabolic stress (i.e., fasting), p53 binds to the PPARGC1A promoter of both human and mouse genes, and this event is positively related to increased PGC-1a expression. This effect was abrogated by inhibiting nitric oxide (NO) synthase or guanylate cyclase, implicating NO/cGMP signaling in such a process. We show that p53-mediated PGC-1a upregulation is directed to potentiate the antioxidant defense through nuclear factor (erythroid-derived 2)-like2 (NFE2L2)-mediated expression of manganese superoxide dismutase (SOD2) and c-glutamylcysteine ligase without modulating mitochondrial biogenesis. Innovation and Conclusions: We outlined a new NO-dependent signaling axis responsible for survival antioxidant response upon mild metabolic stress (fasting) and/or oxidative imbalance (GSH depletion). Such signaling axis could become the cornerstone for new pharmacological or dietary approaches for improving antioxidant response during ageing and human pathologies associated with oxidative stress. Antioxid. Redox Signal. 18, 386-399.

SIRT1 and PGC-1α are two nutrient sensing master regulators of cellular metabolism and their upregulation is often linked to increased lifespan. SIRT1 and PGC-1α modulate the expression of a set of nuclear genes controlling many metabolic pathways. In recent years mounting evidence has indicated the implication of these proteins in several mitochondrial diseases including neurodegenerative disorders, myopathies and Type II diabetes mellitus. Recently, these proteins have been localized in cytoplasm and mitochondria wherein they target novel substrates opening new insight into their possible function in modulating extranuclear genes and proteins. This review will firstly summarize the nuclear function of SIRT1 and PGC-1α. Then, data from papers demonstrating the presence of SIRT1 and PGC-1α in the cytoplasm and in mitochondria will be outlined so that these extranuclear forms do not remain out of sight. Finally, very recent evidence of the alteration of the pathways governed by SIRT1 and PGC-1α in human mitochondrial diseases will be described and the possible role of their mitochondrial forms will be briefly discussed.

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-1α 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-1α activity. The increase of PGC-1α 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-1α in neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1α-governed pathways could be used as target for nutritional intervention to prevent neurodegeneration.

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