The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

Kennedy, Brian K.; Lamming, Dudley W.

doi:10.1016/j.cmet.2016.05.009

Cited by 434 publications

(365 citation statements)

References 170 publications

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“…Such a scenario is supported by the reperfusion signature associated with cellular events (metabolic shift, autophagy, RNA metabolism, ribosomal biogenesis, protein synthesis) activated in response to environmental stress (ischaemic damage, nutrient deprivation and hypoxia), which facilitates cellular repair after insult, or induces apoptosis if the damage is too severe. Recent evidence has indicated that these prosurvival and repair pathways associated with ageing are conserved across taxa, and include the mTOR, AKT and p38 pathways, suggesting that insufficient resolution of the response to peritransplant stresses is associated with dysregulation of cellular homeostasis (Gingell‐Littlejohn et al, 2013); Kennedy & Lamming, 2016; Figure 5). These pathways are critical regulators of cellular metabolism allowing cells to sense and adapt to environmental factors, with some being involved in the regulation of lifespan in model organisms, including mTOR signalling.…”

Section: Discussionmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

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Section: Discussionmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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“…Nitrogen starvation is well known to inhibit TORC1 (13). To directly test whether rewiring of the SUMO proteome depends on TORC1 activity, we treated cells with the TORC1 inhibitor rapamycin.…”

Section: Significancementioning

confidence: 99%

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

Chymkowitch

Aanes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintaining cellular homeostasis under changing nutrient conditions is essential for the growth and development of all organisms. The mechanisms that maintain homeostasis upon loss of nutrient supply are not well understood. By mapping the SUMO proteome in Saccharomyces cerevisiae, we discovered a specific set of differentially sumoylated proteins mainly involved in transcription. RNA polymerase III (RNAPIII) components, including Rpc53, Rpc82, and Ret1, are particularly prominent nutrient-dependent SUMO targets. Nitrogen starvation, as well as direct inhibition of the master nutrient response regulator target of rapamycin complex 1 (TORC1), results in rapid desumoylation of these proteins, which is reflected by loss of SUMO at tRNA genes. TORC1-dependent sumoylation of Rpc82 in particular is required for robust tRNA transcription. Mechanistically, sumoylation of Rpc82 is important for assembly of the RNAPIII holoenzyme and recruitment of Rpc82 to tRNA genes. In conclusion, our data show that TORC1-dependent sumoylation of Rpc82 bolsters the transcriptional capacity of RNAPIII under optimal growth conditions.I n yeast and in more complex eukaryotes, cell growth is restricted by the rate of mRNA translation and ribosome biogenesis, which depend on the transcription of ribosomal protein genes (RPGs), tRNAs and rRNAs. Synthesis of rRNA, tRNAs, and 5S rRNA represents 75% of total cellular transcription, whereas transcription of RPGs corresponds to 50% of RNA polymerase II (RNAPII) initiation events (1). These processes consume a significant portion of the cell's resources, making nutrient availability a limiting factor to cell growth and proliferation (2). The conserved rapamycin-sensitive target of rapamycin complex 1 (TORC1) is a master regulator of the cellular nutrient response (2, 3). Under nitrogen-rich conditions, TORC1 promotes growth-related processes, like protein synthesis, ribosome biogenesis, and tRNA synthesis, while inhibiting catabolic processes, like autophagy (2). Conversely, inhibition of TORC1 activity by nitrogen depletion (or addition of the TORC1 inhibitor rapamycin) results in a metabolic switch from anabolism to catabolism, which involves many cellular processes, including down-regulation of transcription of RPGs, rRNA and tRNA genes (2, 3).A key downstream target of TORC1 in regulation of tRNA transcription is the conserved RNAPIII inhibitor Maf1, which is phosphorylated and maintained in the cytoplasm under nitrogenrich conditions (2, 3). Maf1 becomes hypophosphorylated under conditions that inhibit TORC1, allowing it to enter the nucleus where it associates with TFIIIB. The interaction between Maf1 and TFIIIB prevents the recruitment of RNAPIII and precludes transcription reinitiation at 5S rRNA and tRNA genes (4, 5). However, expression of an unphosphorylatable maf1 mutant does not completely repress tRNA expression in nutrient-replete cells (6), suggesting that dephosphorylation of Maf1 alone is not sufficient to fully inhibit RNAPIII. Indeed, inhibition of TORC1 also results in phospho...

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“…One possible interpretation of this finding is that the levels of mTORC1 signaling are important late in life but not early. This is supported by evidence, still controversial, that mTORC1 signaling may be aberrantly upregulated during the aging process (4). Current studies are inconclusive, and it may be important to consider that mTORC1 signaling is not constant, but nutrient-and stressresponsive.…”

Section: Mtor In Disease and Agingmentioning

confidence: 50%

“…The mammalian target of rapamycin (mTOR) has since been studied extensively throughout the landscape of eukaryotic species (a recent PubMed search of "mTOR" revealed nearly 20,000 papers) (3)(4)(5). Authors of several recent reviews described the pathway in detail; in this article, we provide only a brief overview.…”

mentioning

confidence: 99%