Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy

Rhianna C. Laker, Joshua C. Drake, Rebecca J. Wilson, Vitor A. Lira, Bevan M. Lewellen, Karen A. Ryall, Carleigh C. Fisher, Mei Zhang, Jeffrey J. Saucerman, Laurie J. Goodyear, Mondira Kundu and Zhen Yan ()
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Rhianna C. Laker: University of Virginia School of Medicine
Joshua C. Drake: University of Virginia School of Medicine
Rebecca J. Wilson: University of Virginia School of Medicine
Vitor A. Lira: University of Virginia School of Medicine
Bevan M. Lewellen: University of Virginia School of Medicine
Karen A. Ryall: University of Virginia School of Medicine
Carleigh C. Fisher: University of Virginia School of Medicine
Mei Zhang: University of Virginia School of Medicine
Jeffrey J. Saucerman: University of Virginia School of Medicine
Laurie J. Goodyear: Brigham and Women’s Hospital and Harvard Medical School
Mondira Kundu: St. Jude Children’s Research Hospital
Zhen Yan: University of Virginia School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3–12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.

Date: 2017
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DOI: 10.1038/s41467-017-00520-9

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