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Sestrin2-AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity.
Cell Signal. 2015 Jul; 27(7):1533-43.CS

Abstract

Sestrin2 (SESN2) regulates redox-homeostasis and apoptosis in response to various stresses. Although the antioxidant effects of SESN2 have been well established, the roles of SESN2 in mitochondrial function and metabolic stress have not yet been elucidated. In this study, we investigated the role of SESN2 in mitochondrial dysfunction under glucose deprivation and related signaling mechanisms. Glucose deprivation significantly upregulated SESN2 expression in hepatocyte-derived cells. Antioxidant treatments repressed SESN2 induction under glucose deprivation, this result suggested that reactive oxygen species (ROS) production was involved in SESN2 induction. Moreover, NF-E2-related factor-2 (Nrf2) phosphorylation was accompanied in induction of SESN2 by glucose deprivation. To elucidate the functional role of SESN2, we examined cells that stably overexpressed SESN2. Overexpression of SESN2 inhibited glucose deprivation-induced ROS production and cell death. In addition, under glucose deprivation, the changes in mitochondrial membrane potential, ADP/ATP ratio, and mitochondrial DNA content were significantly restored in SESN2-overexpressing cells. Moreover, siRNA knockdown of SESN2 failed to prevent mitochondrial permeability transition by glucose depletion. Mechanistic investigation showed that glucose deprivation significantly increased AMP-activated protein kinase (AMPK) activation. The recovery of mitochondrial function under glucose deprivation in SESN2-overexpressing cells was not seen in SESN2-overexpressing cells transfected with a dominant-negative AMPK; this result suggested that AMPK activation was responsible for SESN2-mediated mitochondrial protection against glucose deprivation. Treatment with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an AMPK activator) also provided cytoprotective effects against glucose deprivation. Our findings provide evidence for the functional importance of SESN2-AMPK activation in the protection of mitochondria and cells against glucose deprivation-induced metabolic stress.

Authors+Show Affiliations

College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.College of Pharmacy, Chosun University, Gwangju 501-759, South Korea. Electronic address: smshin@chosun.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

25778901

Citation

Seo, Kyuhwa, et al. "Sestrin2-AMPK Activation Protects Mitochondrial Function Against Glucose Deprivation-induced Cytotoxicity." Cellular Signalling, vol. 27, no. 7, 2015, pp. 1533-43.
Seo K, Ki SH, Shin SM. Sestrin2-AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity. Cell Signal. 2015;27(7):1533-43.
Seo, K., Ki, S. H., & Shin, S. M. (2015). Sestrin2-AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity. Cellular Signalling, 27(7), 1533-43. https://doi.org/10.1016/j.cellsig.2015.03.003
Seo K, Ki SH, Shin SM. Sestrin2-AMPK Activation Protects Mitochondrial Function Against Glucose Deprivation-induced Cytotoxicity. Cell Signal. 2015;27(7):1533-43. PubMed PMID: 25778901.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sestrin2-AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity. AU - Seo,Kyuhwa, AU - Ki,Sung Hwan, AU - Shin,Sang Mi, Y1 - 2015/03/14/ PY - 2015/01/28/received PY - 2015/03/03/accepted PY - 2015/3/18/entrez PY - 2015/3/18/pubmed PY - 2016/2/18/medline KW - AMPK KW - Glucose deprivation KW - Hepatocytes KW - Mitochondria KW - Reactive oxygen species KW - Sestrin2 SP - 1533 EP - 43 JF - Cellular signalling JO - Cell. Signal. VL - 27 IS - 7 N2 - Sestrin2 (SESN2) regulates redox-homeostasis and apoptosis in response to various stresses. Although the antioxidant effects of SESN2 have been well established, the roles of SESN2 in mitochondrial function and metabolic stress have not yet been elucidated. In this study, we investigated the role of SESN2 in mitochondrial dysfunction under glucose deprivation and related signaling mechanisms. Glucose deprivation significantly upregulated SESN2 expression in hepatocyte-derived cells. Antioxidant treatments repressed SESN2 induction under glucose deprivation, this result suggested that reactive oxygen species (ROS) production was involved in SESN2 induction. Moreover, NF-E2-related factor-2 (Nrf2) phosphorylation was accompanied in induction of SESN2 by glucose deprivation. To elucidate the functional role of SESN2, we examined cells that stably overexpressed SESN2. Overexpression of SESN2 inhibited glucose deprivation-induced ROS production and cell death. In addition, under glucose deprivation, the changes in mitochondrial membrane potential, ADP/ATP ratio, and mitochondrial DNA content were significantly restored in SESN2-overexpressing cells. Moreover, siRNA knockdown of SESN2 failed to prevent mitochondrial permeability transition by glucose depletion. Mechanistic investigation showed that glucose deprivation significantly increased AMP-activated protein kinase (AMPK) activation. The recovery of mitochondrial function under glucose deprivation in SESN2-overexpressing cells was not seen in SESN2-overexpressing cells transfected with a dominant-negative AMPK; this result suggested that AMPK activation was responsible for SESN2-mediated mitochondrial protection against glucose deprivation. Treatment with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an AMPK activator) also provided cytoprotective effects against glucose deprivation. Our findings provide evidence for the functional importance of SESN2-AMPK activation in the protection of mitochondria and cells against glucose deprivation-induced metabolic stress. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/25778901/Sestrin2_AMPK_activation_protects_mitochondrial_function_against_glucose_deprivation_induced_cytotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(15)00089-3 DB - PRIME DP - Unbound Medicine ER -