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 G. Kohama, E. Dale Abel, Myung K. Kim, Jay H. Chung

Research output: Contribution to journalArticle

25 Scopus citations

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

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

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  • Cite this

    Park, S. J., Gavrilova, O., Brown, A. L., Soto, J. E., Bremner, S., Kim, J., Xu, X., Yang, S., Um, J. H., Koch, L. G., Britton, S. L., Lieber, R. L., Philp, A., Baar, K., Kohama, S. G., Abel, E. D., Kim, M. K., & 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