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Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney.

Authors :
Kume, Shinji
Uzu, Takashi
Horiike, Kihachiro
Chin-Kanasaki, Masami
Isshiki, Keiji
Araki, Shin-ichi
Sugimoto, Toshiro
Haneda, Masakazu
Kashiwagi, Atsunori
Koya, Daisuke
Source :
Journal of Clinical Investigation. Apr2010, Vol. 120 Issue 4, p1043-1055. 13p. 1 Color Photograph, 4 Black and White Photographs, 1 Diagram, 8 Graphs.
Publication Year :
2010

Abstract

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219738
Volume :
120
Issue :
4
Database :
Academic Search Index
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
49049751
Full Text :
https://doi.org/10.1172/JCI41376