Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics

• Published in: Cell metabolism Vol. 27; no. 3; pp. 657 - 666.e5
• Main Authors: Schmitt, Karen, Grimm, Amandine, Dallmann, Robert, Oettinghaus, Bjoern, Restelli, Lisa Michelle, Witzig, Melissa, Ishihara, Naotada, Mihara, Katsuyoshi, Ripperger, Jürgen A., Albrecht, Urs, Frank, Stephan, Brown, Steven A., Eckert, Anne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-03-2018
• Subjects: bioenergetics; circadian clock; DRP1; dynamics; fission; fusion; glycolysis; metabolism; mitochondria; oxidative phosphorylation; fusion; dynamics; bioenergetics; mitochondria; fission; glycolysis; metabolism; circadian clock; oxidative phosphorylation; DRP1
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.01.011

Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondrial network and circadian cycles.
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•The circadian clock controls rhythmic mitochondrial dynamics and metabolic flux•DRP1 is phosphorylated in circadian fashion•Suppression of DRP1 activity eliminates circadian ATP production•Blocking DRP1 function impairs the core circadian clock
Schmitt et al. demonstrate that the circadian clock globally regulates mitochondrial morphology and energy metabolism. Even in non-dividing tissues, rhythmic control of DRP1 phosphorylation directs circadian mitochondrial morphology. This control is not only essential for circadian ATP production but also feeds back to influence the core circadian clock.