Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics

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

doi:10.1016/j.cmet.2018.01.011

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Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics

Schmitt, Karen 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, Switzerland
Grimm, Amandine 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, Switzerland
Dallmann, Robert Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zurich, Switzerland
Oettinghaus, Bjoern Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland
Restelli, Lisa Michelle Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland
Witzig, Melissa 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, Switzerland
Ishihara, Naotada Department of Protein Biochemistry, Institute of Life Science, Kurume University, Japan
Mihara, Katsuyoshi Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
Ripperger, Jürgen A. Department of Biology, Unit of Biochemistry, University of Fribourg, Switzerland
Albrecht, Urs Department of Biology, Unit of Biochemistry, University of Fribourg, Switzerland
Frank, Stephan Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland
Brown, Steven A. Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zurich, Switzerland
Eckert, Anne 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, Switzerland

06.03.2018

Published in:

Cell Metabolism. - 2018, vol. 27, no. 3, p. 657-666.e5

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language