Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics

Publication date: Available online 22 February 2018
Source:Cell Metabolism
Author(s): Karen Schmitt, Amandine Grimm, Robert Dallmann, Bjoern Oettinghaus, Lisa Michelle Restelli, Melissa Witzig, Naotada Ishihara, Katsuyoshi Mihara, Jürgen A. Ripperger, Urs Albrecht, Stephan Frank, Steven A. Brown, Anne Eckert
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.

Graphical abstract

Teaser

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.


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