Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics

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.

Notch1 protects against myocardial ischaemia‐reperfusion injury via regulating mitochondrial fusion and function

“…The two major proteins involved in mammalian mitochondrial fission are Fis1 and Drp1 . Fis1 is an adaptor protein located in the outer mitochondrial membrane, whereas Drp1 is localized in the cytosol, from where it shuttles back and forth to the outer mitochondrial membrane during fission events . Notch was reported to up‐regulate MFN2 expression through the cascade‐up effect of NICD/Akt/Mfn and promote mitochondrial fission .…”

“…31 Fis1 is an adaptor protein located in the outer mitochondrial membrane, whereas Drp1 is localized in the cytosol, from where it shuttles back and forth to the outer mitochondrial membrane during fission events. 32,33 Notch was reported to up-regulate MFN2 expression through the cascade-up effect of NICD/Akt/Mfn and promote mitochondrial fission. 26,27 On the other hand, it down-regulates Drp1 expression and inhibits F I G U R E 5 Notch1 improves the mitochondrial membrane potential in myocardiocytes exposed to IRI.…”

PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria

“…A recent paper showed that Drp1-dependent mitochondrial dynamic was coupled with oxidative respiration: tubular mitochondria was accompanied with increased oxidative respiration, while fragmented mitochondria achieved the opposite [37]. The oxidative phosphorylation activity was supposed to be required in the RLR innate immune signaling, as SeV-induced IFN production was impaired in cells with oxidative phosphorylation defect, but was restored when the oxidative phosphorylation was recovered [38].…”

Tracking intra‐ and inter‐organelle signaling of mitochondria

“…The mitochondrial network is a highly specialized working unit capable of undergoing dynamic adaptation in order to meet metabolic needs and to allow internal and external signaling . Thereby, constant fission and fusion of the inner (IMM) and outer mitochondrial membrane (OMM) play a crucial role in maintaining mitochondrial integrity.…”

“…Mitochondria have undergone a drastic transition from free‐living bacteria to fundamental compartments within eukaryotic cells . Therefore, the mitochondria's broad field of contributions, ranging from production of ATP by oxidative phosphorylation (OXPHOS), buffering of Ca 2+ , and contribution to various cellular signaling pathways, was supplemented with highly dynamic structural and functional adaptations . Stretching throughout the cell as a highly dynamic network along the cytoskeleton, mitochondria are constantly undergoing fusion and fission to meet the requirements of cellular subdomains under various conditions , as discussed in our ‘Mitochondria as highly specialized working unit’ section.…”