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Cell Metab. 2018 Mar 6;27(3):657-666.e5. doi: 10.1016/j.cmet.2018.01.011. Epub 2018 Feb 22.

Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics.

Author information

1
Neurobiology Lab for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Basel, Switzerland; Psychiatric University Clinics, University of Basel, Basel, Switzerland.
2
Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
3
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
4
Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan.
5
Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
6
Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg, Switzerland.
7
Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland. Electronic address: steven.brown@pharma.uzh.ch.
8
Neurobiology Lab for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Basel, Switzerland; Psychiatric University Clinics, University of Basel, Basel, Switzerland. Electronic address: anne.eckert@upkbs.ch.

Abstract

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.

KEYWORDS:

DRP1; bioenergetics; circadian clock; dynamics; fission; fusion; glycolysis; metabolism; mitochondria; oxidative phosphorylation

PMID:
29478834
DOI:
10.1016/j.cmet.2018.01.011
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