Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics

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 mito...

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Bibliographic Details
Published in:Cell metabolism 2018-03, Vol.27 (3), p.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: Article
Language:English
Subjects:
bioenergetics
circadian clock
DRP1
dynamics
fission
fusion
glycolysis
metabolism
mitochondria
oxidative phosphorylation
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Summary: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. [Display omitted] •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.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2018.01.011