PGC‐1a integrates a metabolism and growth network linked to caloric restriction

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.

Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

“…The inference is a shift toward fatty acid fuel utilization, aligning with prior reports of lipid remodeling outcomes reported in renal endothelial cells (Choi et al, 2018). These outcomes are also consistent with our genetic studies of modest PGC-1a overexpression in preadipocytes, where these same metabolic changes induced in mitochondria were linked to greater capacity for lipid fuel utilization, changes in lipid handling, lipid storage, and membrane lipid composition (Miller et al, 2019b). Anti-inflammatory actions of AdipoRon could also exert beneficial muscle outcomes as recently reported in a genetic mice model of Duchenne muscular dystrophy and warrants investigation in our aging study (Abou-Samra et al, 2020).…”

“…5D). Our previous studies have shown that increased respiration is accompanied by slower growth in cultured fibroblasts (Miller et al, 2019b).…”

“…5E). We had previously shown that mitochondrial organization is influenced by chronic elevation of PGC-1a (Miller et al, 2019b). Mitochondria were visualized in fixed fibroblasts by immunofluorescence detection of TOMM20 following 24 hrs AdipoRon treatment (Fig.…”

Norisoboldine Attenuates Sepsis-Induced Acute Lung Injury by Modulating Macrophage Polarization <i>via</i> PKM2/HIF-1α/PGC-1α Pathway

“…44) PKM2 activators can promote the formation of its tetramer, reduce nuclear transcription, inhibit the production of pro-inflammatory M1-type macrophages induced by LPS, and promote the production of anti-inflammatory M2type macrophages. 46,47) Our data indicated that NOR could inhibit the increase of PKM2 nuclear transcription and HIF-1α expression induced by LPS, which may be the underlying mechanism of activating M2-type macrophages. PGC-1α plays an important role in oxidative metabolism, promoting oxidative phosphorylation and mitochondrial proliferation.…”

Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys

“…Growth pathways are integral in cell fate, functional dynamics including cytoskeleton assembly and organization, energetics, and growth. Studies in cells and in tissues of genetically diverse mice confirm the integration of metabolism and growth networks and indicate that mitochondria might be drivers rather than passengers in the aging process (Miller et al, 2019). An emerging theme from our work and that of others is the complex interplay between metabolic and growth regulation where changes in each define the range of response in the other, and both are coordinated through nutrient availability and nutrient-sensitive signaling (Bartke, 2017;Finkel, 2015;Ma and Gladyshev, 2017;Souder and Anderson, 2019).…”