ABSTRACT
Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC‐1a is induced by CR in multiple tissues, and at the cellular level, CR‐like activation of PGC‐1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC‐1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post‐transcriptional and post‐translational mechanisms were also identified as outcomes of PGC‐1a‐directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC‐1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC‐1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.
INTRODUCTION
Mitochondrial dysfunction is a prominent feature of aging at the cellular level and includes reduced bioenergetic efficiency and loss of integrity of mitochondrial‐dependent processes linked to cell fate (Sun, Youle, & Finkel, 2016). Numerous studies have reported a decline in expression of nuclear‐encoded genes of the electron transport chain (ETC) with age, and this feature is shared across multiple organisms (McCarroll et al., 2004; Zahn et al., 2006). In mammals, ETC genes are direct or indirect targets of the PGC‐1 (peroxisome proliferator‐activated receptor gamma‐coactivator 1) family of transcription factors. These master regulators of mitochondrial function include PGC‐1a (gene symbol Ppargc1a), PGC‐1b (gene symbol Ppargc1b), and PRC (PGC‐1‐related coactivator; gene symbol Pprc1) (Villena, 2015), although PGC‐1a is by far the best characterized with expression ubiquitous among tissues (Martinez‐Redondo et al., 2016). The pace of aging and incidence of age‐related disease is offset by the dietary intervention of caloric restriction (CR) (Balasubramanian, Howell, & Anderson, 2017). A meta‐analysis study of CR‐induced changes in gene expression identified mitochondrial pathways as the dominant feature in a conserved tissue type‐independent transcriptional signature (Barger et al., 2015), suggesting that PGC‐1a could be a potential target for the development of CR mimetics. Much of the early studies of the biology of PGC‐1a involved relatively high levels of overexpression and focused on exercise or thermogenesis (Scarpulla, 2011). Physiologically, CR interventions in mouse and human studies show modest yet consistent increases in PGC‐1a expression in adipose tissues and liver (Anderson et al., 2008; Corton et al., 2004; Fujii et al., 2017; Nisoli et al., 2005) with less consistent effects reported in skeletal muscle (Gouspillou & Hepple, 2013). Similarly, elevated PGC‐1a expression in adipose and liver in mammalian genetic models of longevity is consistent with enhanced mitochondrial function and efficiency (Bartke & Darcy, 2017). More recently, genetic studies suggest that the actual physiological role of PGC‐1a in adult animals is in adaptation to changes in energy availability or demand rather than maintenance of basal energetics (Villena, 2015). The small but consistent activation of mitochondrial pathways observed with CR is compatible with this newer view of PGC‐1a function. Surprisingly, our knowledge of the function of endogenous PGC‐1a remains quite limited, and the broader consequence of small changes in PGC‐1a status is largely uncharacterized. The goal of this study was to fill in some of these gaps. Specifically, we sought to test whether PGC‐1a activation might be sufficient to mimic CR’s effects, to determine the cellular consequence of modest but persistently augmented PGC‐1a levels, and to identify connections between physiological perturbations of PGC‐1a and metabolism and growth pathways linked to longevity and CR.
FIGURE 1 Moderate, stable PGC‐1a overexpression is associated with a large transcriptional network. (a) Detection of PGC‐1a isoform expression in tissues from 12‐month‐old mice on 25% CR from 2 months of age. (b) Ranked fold change of all detected genes between control and PGC‐OE cells and © fold change as a function of mean expression with differentially expressed (DE) genes in red (p < 0.01, absolute FC > 1.2), n = 4. (d) KEGG pathway analysis. (e) Proportion of genes with multiple annotated transcript isoforms. (f) Rank ordered KEGG pathways by enrichment score; colors indicate panel © categories. (g) ENCODE factors associated with upregulated (red) and downregulated (blue) DE genes. (h) Fold change of histone H3K27 and K36 methylation and (i) quantitation of histone acetylation by mass spectrometry, n = 6. Pan, pan‐PGC‐1a isoform expression; 1a1, PGC‐1a1 isoform, etc. Data shown as means ± SEM; asterisk (*) indicates p < 0.05 by two‐tailed Student's t test.
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Edited by Engadin, 08 July 2019 - 12:22 PM.
