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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2017 May 4

PMID 28467930

Citations 54

Authors

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

Affiliations

Soon will be listed here.

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.

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