Autophagy in premature senescent cells is activated via AMPK pathway

Liujing Guo; Bushan Xie; Zebin Mao

doi:10.3390/ijms13033563

Autophagy in premature senescent cells is activated via AMPK pathway

Int J Mol Sci. 2012;13(3):3563-3582. doi: 10.3390/ijms13033563. Epub 2012 Mar 16.

Authors

Liujing Guo¹, Bushan Xie², Zebin Mao¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
² Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China.

Abstract

Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. In this study, we show that the activity of autophagy increases in H(2)O(2) or RasV12-induced senescent fibroblasts. Inhibiting autophagy promotes cell apoptosis in senescent cells, suggesting that autophagy activation plays a cytoprotective role. Furthermore, our data indicate that the increase of autophagy in senescent cells is linked to the activation of transcription factor FoxO3A, which blocks ATP generation by transcriptionally up-regulating the expression of PDK4, an inhibitor of pyruvate dehydrogenase complex, thus leading to AMPK activation and mTOR inhibition. These findings suggest a novel mechanism by which FoxO3A factors can activate autophagy via metabolic alteration.

Keywords: AMPK; FoxO3A; apoptosis; autophagy; fibroblasts; senescent cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / biosynthesis
AMP-Activated Protein Kinases / metabolism*
Adenosine Triphosphate / biosynthesis
Apoptosis
Autophagy / physiology*
Cell Proliferation
Cells, Cultured
Cellular Senescence / physiology*
Enzyme Activation
Fibroblasts / cytology
Fibroblasts / pathology
Forkhead Box Protein O3
Forkhead Transcription Factors / biosynthesis
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Humans
Hydrogen Peroxide / pharmacology
Protein Serine-Threonine Kinases / biosynthesis*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Pyruvate Dehydrogenase Complex / antagonists & inhibitors
RNA Interference
RNA, Small Interfering
Signal Transduction
TOR Serine-Threonine Kinases / antagonists & inhibitors

Substances

FOXO3 protein, human
Forkhead Box Protein O3
Forkhead Transcription Factors
PDK4 protein, human
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Pyruvate Dehydrogenase Complex
RNA, Small Interfering
Adenosine Triphosphate
Hydrogen Peroxide
MTOR protein, human
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases