Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy

Joshua C. Drake (Lead / Corresponding author), Rebecca J. Wilson, Rhianna C. Laker, Yuntian Guan, Hannah R. Spaulding, Anna S. Nichenko, Wenqing Shen, Huayu Shang, Maya V. Dorn, Kian Huang, Mei Zhang, Aloka B. Bandara, Matthew H. Brisendine, Jennifer A. Kashatus, Poonam R. Sharma, Alexander Young, Jitendra Gautam, Ruofan Cao, Horst Wallrabe, Paul A. ChangMichael Wong, Eric M. Desjardins, Simon A. Hawley, George J. Christ, David F. Kashatus, Clint L. Miller, Matthew J. Wolf, Ammasi Periasamy, Gregory R. Steinberg, D. Grahame Hardie, Zhen Yan (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)
68 Downloads (Pure)


Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Original languageEnglish
Article numbere2025932118
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
Early online date7 Sept 2021
Publication statusPublished - 14 Sept 2021


  • mitochonria
  • AMPK
  • skeletal muscle
  • exercise
  • mitophagy
  • Mitochondria
  • Exercise
  • Mitophagy
  • Skeletal muscle

ASJC Scopus subject areas

  • General


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