DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging

Sung Jun Park, Oksana Gavrilova, Alexandra L. Brown, Jamie E. Soto, Shannon Bremner, Jeonghan Kim, Xihui Xu, Shutong Yang, Jee Hyun Um, Lauren G. Koch, Steven L. Britton, Richard L. Lieber, Andrew Philp, Keith Baar, Steven Kohama, E. Dale Abel, Myung K. Kim, Jay H. Chung

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.

    Original languageEnglish (US)
    Pages (from-to)1135-1146.e7
    JournalCell Metabolism
    Volume25
    Issue number5
    DOIs
    StatePublished - May 2 2017

    Fingerprint

    DNA-Activated Protein Kinase
    Physical Fitness
    AMP-Activated Protein Kinases
    Type 2 Diabetes Mellitus
    Energy Metabolism
    Weight Gain
    DNA Breaks
    Organelle Biogenesis
    Threonine
    Protein Kinase Inhibitors
    Insulin Resistance
    Skeletal Muscle
    Obesity
    Health

    Keywords

    • aging
    • AMPK
    • calorie restriction
    • DNA-PK
    • exercise
    • HSP90α
    • insulin sensitivity
    • mitochondria
    • obesity
    • skeletal muscle
    • type 2 diabetes

    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology

    Cite this

    Park, S. J., Gavrilova, O., Brown, A. L., Soto, J. E., Bremner, S., Kim, J., ... Chung, J. H. (2017). DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metabolism, 25(5), 1135-1146.e7. https://doi.org/10.1016/j.cmet.2017.04.008

    DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. / Park, Sung Jun; Gavrilova, Oksana; Brown, Alexandra L.; Soto, Jamie E.; Bremner, Shannon; Kim, Jeonghan; Xu, Xihui; Yang, Shutong; Um, Jee Hyun; Koch, Lauren G.; Britton, Steven L.; Lieber, Richard L.; Philp, Andrew; Baar, Keith; Kohama, Steven; Abel, E. Dale; Kim, Myung K.; Chung, Jay H.

    In: Cell Metabolism, Vol. 25, No. 5, 02.05.2017, p. 1135-1146.e7.

    Research output: Contribution to journalArticle

    Park, SJ, Gavrilova, O, Brown, AL, Soto, JE, Bremner, S, Kim, J, Xu, X, Yang, S, Um, JH, Koch, LG, Britton, SL, Lieber, RL, Philp, A, Baar, K, Kohama, S, Abel, ED, Kim, MK & Chung, JH 2017, 'DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging', Cell Metabolism, vol. 25, no. 5, pp. 1135-1146.e7. https://doi.org/10.1016/j.cmet.2017.04.008
    Park SJ, Gavrilova O, Brown AL, Soto JE, Bremner S, Kim J et al. DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metabolism. 2017 May 2;25(5):1135-1146.e7. https://doi.org/10.1016/j.cmet.2017.04.008
    Park, Sung Jun ; Gavrilova, Oksana ; Brown, Alexandra L. ; Soto, Jamie E. ; Bremner, Shannon ; Kim, Jeonghan ; Xu, Xihui ; Yang, Shutong ; Um, Jee Hyun ; Koch, Lauren G. ; Britton, Steven L. ; Lieber, Richard L. ; Philp, Andrew ; Baar, Keith ; Kohama, Steven ; Abel, E. Dale ; Kim, Myung K. ; Chung, Jay H. / DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. In: Cell Metabolism. 2017 ; Vol. 25, No. 5. pp. 1135-1146.e7.
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