Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1

Yanhua Yao, Scott Tsuchiyama, Ciyu Yang, Anne Laure Bulteau, Chong He, Brett Robison, Mitsuhiro Tsuchiya, Delana Miller, Valeria Briones, Krisztina Tar, Anahi Potrero, Bertrand Friguet, Brian K. Kennedy, Marion Schmidt

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Elevated proteasome activity extends lifespan in model organisms such as yeast, worms and flies. This pro-longevity effect might be mediated by improved protein homeostasis, as this protease is an integral module of the protein homeostasis network. Proteasomes also regulate cellular processes through temporal and spatial degradation of signaling pathway components. Here we demonstrate that the regulatory function of the proteasome plays an essential role in aging cells and that the beneficial impact of elevated proteasome capacity on lifespan partially originates from deregulation of the AMPK signaling pathway. Proteasome-mediated lifespan extension activity was carbon-source dependent and cells with enhancement proteasome function exhibited increased respiratory activity and oxidative stress response. These findings suggested that the pro-aging impact of proteasome upregulation might be related to changes in the metabolic state through a premature induction of respiration. Deletion of yeast AMPK, SNF1, or its activator SNF4 abrogated proteasome-mediated lifespan extension, supporting this hypothesis as the AMPK pathway regulates metabolism. We found that the premature induction of respiration in cells with increased proteasome activity originates from enhanced turnover of Mig1, an AMPK/Snf1 regulated transcriptional repressor that prevents the induction of genes required for respiration. Increasing proteasome activity also resulted in partial relocation of Mig1 from the nucleus to the mitochondria. Collectively, the results argue for a model in which elevated proteasome activity leads to the uncoupling of Snf1-mediated Mig1 regulation, resulting in a premature activation of respiration and thus the induction of a mitohormetic response, beneficial to lifespan. In addition, we observed incorrect Mig1 localization in two other long-lived yeast aging models: cells that overexpress SIR2 or deleted for the Mig1-regulator HXK2. Finally, compromised proteasome function blocks lifespan extension in both strains. Thus, our findings suggest that proteasomes, Sir2, Snf1 and Hxk2 form an interconnected aging network that controls metabolism through coordinated regulation of Mig1.

Original languageEnglish (US)
Article numbere1004968
JournalPLoS Genetics
Volume11
Issue number1
DOIs
StatePublished - 2015

Fingerprint

AMP-Activated Protein Kinases
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
respiration
yeast
homeostasis
metabolism
cell respiration
protein
deregulation
mitochondrion
relocation
turnover
Respiration
Yeasts
Cell Aging
yeasts
degradation
gene
carbon

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1. / Yao, Yanhua; Tsuchiyama, Scott; Yang, Ciyu; Bulteau, Anne Laure; He, Chong; Robison, Brett; Tsuchiya, Mitsuhiro; Miller, Delana; Briones, Valeria; Tar, Krisztina; Potrero, Anahi; Friguet, Bertrand; Kennedy, Brian K.; Schmidt, Marion.

In: PLoS Genetics, Vol. 11, No. 1, e1004968, 2015.

Research output: Contribution to journalArticle

Yao, Y, Tsuchiyama, S, Yang, C, Bulteau, AL, He, C, Robison, B, Tsuchiya, M, Miller, D, Briones, V, Tar, K, Potrero, A, Friguet, B, Kennedy, BK & Schmidt, M 2015, 'Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1', PLoS Genetics, vol. 11, no. 1, e1004968. https://doi.org/10.1371/journal.pgen.1004968
Yao, Yanhua ; Tsuchiyama, Scott ; Yang, Ciyu ; Bulteau, Anne Laure ; He, Chong ; Robison, Brett ; Tsuchiya, Mitsuhiro ; Miller, Delana ; Briones, Valeria ; Tar, Krisztina ; Potrero, Anahi ; Friguet, Bertrand ; Kennedy, Brian K. ; Schmidt, Marion. / Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1. In: PLoS Genetics. 2015 ; Vol. 11, No. 1.
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abstract = "Elevated proteasome activity extends lifespan in model organisms such as yeast, worms and flies. This pro-longevity effect might be mediated by improved protein homeostasis, as this protease is an integral module of the protein homeostasis network. Proteasomes also regulate cellular processes through temporal and spatial degradation of signaling pathway components. Here we demonstrate that the regulatory function of the proteasome plays an essential role in aging cells and that the beneficial impact of elevated proteasome capacity on lifespan partially originates from deregulation of the AMPK signaling pathway. Proteasome-mediated lifespan extension activity was carbon-source dependent and cells with enhancement proteasome function exhibited increased respiratory activity and oxidative stress response. These findings suggested that the pro-aging impact of proteasome upregulation might be related to changes in the metabolic state through a premature induction of respiration. Deletion of yeast AMPK, SNF1, or its activator SNF4 abrogated proteasome-mediated lifespan extension, supporting this hypothesis as the AMPK pathway regulates metabolism. We found that the premature induction of respiration in cells with increased proteasome activity originates from enhanced turnover of Mig1, an AMPK/Snf1 regulated transcriptional repressor that prevents the induction of genes required for respiration. Increasing proteasome activity also resulted in partial relocation of Mig1 from the nucleus to the mitochondria. Collectively, the results argue for a model in which elevated proteasome activity leads to the uncoupling of Snf1-mediated Mig1 regulation, resulting in a premature activation of respiration and thus the induction of a mitohormetic response, beneficial to lifespan. In addition, we observed incorrect Mig1 localization in two other long-lived yeast aging models: cells that overexpress SIR2 or deleted for the Mig1-regulator HXK2. Finally, compromised proteasome function blocks lifespan extension in both strains. Thus, our findings suggest that proteasomes, Sir2, Snf1 and Hxk2 form an interconnected aging network that controls metabolism through coordinated regulation of Mig1.",
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AU - Yang, Ciyu

AU - Bulteau, Anne Laure

AU - He, Chong

AU - Robison, Brett

AU - Tsuchiya, Mitsuhiro

AU - Miller, Delana

AU - Briones, Valeria

AU - Tar, Krisztina

AU - Potrero, Anahi

AU - Friguet, Bertrand

AU - Kennedy, Brian K.

AU - Schmidt, Marion

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