Abstract

Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation.

Highlights

  • Mitochondria are dynamic organelles in the process of division and fusion and play crucial roles in many physiological functions, such as energy production, metabolites synthesis, calcium signaling, cell proliferation and death (Chan, 2012; Nunnari and Suomalainen, 2012)

  • Immunofluorescence staining showed that Dynamic-related protein 1 (DRP1) protein is localized in the cytoplasm of preimplantation embryos (Figure 1B), and the fluorescence intensity of DRP1 is strongest in the zygote stage and became weakest in the blastocyst stage (Figures 1B,C)

  • Mitochondrial division inhibitor-1 (Mdivi-1), a mitochondrial fission inhibitor to treat various diseases related to mitochondrial fission, could lead to mitochondrial dysfunction by DRP1 deficiencyinduced abnormal mitochondrial fission and defective assembly of the electron transport chain complexes

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Summary

Introduction

Mitochondria are dynamic organelles in the process of division and fusion and play crucial roles in many physiological functions, such as energy production, metabolites synthesis, calcium signaling, cell proliferation and death (Chan, 2012; Nunnari and Suomalainen, 2012). Mitochondrial fission is controlled by dynamin-related protein 1 (Drp1) (Youle and van der Bliek, 2012), which encodes the dynamin family and is recruited onto mitochondria at sites marked by endoplasmic reticulum tubules by mitochondrial dynamics factors 49 and 51, fission protein 1 or mitochondrial fission factor (Loson et al, 2013). DRP1 Regulates Zygotic Genome Activation (OPA1) (Youle and van der Bliek, 2012). Brainspecific Drp knockout resulted in enhanced sensorimotor gating and ectopic dendrite formation in mice (Itoh et al, 2019). Cardiacspecific Drp knockout caused left ventricular dysfunction and death within 13 weeks in mice (Ikeda et al, 2015). Drp knockdown negatively influenced cell differentiation, proliferation and led to mitochondrial elongation and cell death (Uo et al, 2009; Wang et al, 2014; Parker et al, 2015)

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