Peroxisome Proliferator-activated Receptor γ Co-activator 1α (PGC-1α) and Sirtuin 1 (SIRT1) Reside in Mitochondria

Abstract

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...

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

“…Several peptides could be excluded as representing physiological substrates due to different cellular localizations of sirtuin and target, but we refrained from correcting the hit lists (Supplementary Data 1), as protein localization annotations are sometimes unreliable, and because sirtuin isoform localization seems to be complex 29,30 . Yet, we also listed for each sirtuin the top 12 hits from proteins known to exist in the same compartment (Supplementary Data 7) and focused the following description of substrate and target pathway candidates (Fig.…”

L’AMPK, régulateur de l’énergie et des fonctions des spermatozoïdes

“…Pourtant, l'AMPK est impliquée dans le renouvellement du contenu mitochondrial des cellules. Elle stimule en effet la dégradation des mitochondries défectueuses par l'intermédiaire d'ULK1/2 (Unc51-like kinase), une kinase associée au processus d'autophagie, et en activant la biogenèse de nouvelles mitochondries, via PGC1α (peroxisome proliferatoractivated receptor γ coactivator 1a) impliqué dans leur régulation, et donc, indirectement, les systèmes antioxydants [42,43]. Mais la stimulation de la régénération du NADPH par l'AMPK [44], par la voie des pentoses phosphates, mise en évidence dans les spermatozoïdes de mammifères, et qui contribue au système antioxydant par la stimulation de la GPx (NADPH-dependent glutathione peroxidase-like protein), pourrait également avoir un rôle dans cette fonction.…”

FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

“…SIRT1, for example, is localized in the cytoplasm of certain tissues 37 but has also been detected in mitochondria. 38 Most sirtuins exert their biological function through the deacetylation of acetylated proteins, which comprise histone and nonhistone proteins 16,17,32 ( Figure 3A). The deacetylation reaction requires the cofactor NAD ϩ and involves the transfer of an acetyl group from an acetylated protein substrate to the ADP-ribose moiety of NAD ϩ .…”