MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria-dependent dephosphorylation of EGFR

Background:Clear cell renal cell carcinoma(ccRCC)is the most lethal renal cancer.An overwhelming increase of patients experience tumor progression and unfavorable prognosis.However,the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear.Therefore,uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC.In this study,we sought to investigate the role of mitofusin-2(MFN2)in supressing ccRCC tumorigenesis and metastasis.Methods:The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort.Both in vitro and in vivo experiments,including cell proliferation,xenograft mouse models and transgenic mouse model,were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC.RNA-sequencing,mass spectrum analysis,co-immunoprecipitation,bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2.Results:we reported a tumor-suppressing pathway in ccRCC,characterized by mitochondria-dependent inactivation of epidermal growth factor receptor(EGFR)signaling.This process was mediated by the outer mitochondrial membrane(OMM)protein MFN2.MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients.in vivo and in vitro assays demonstrated thatMFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway.In a kidney-specific knockout mouse model,loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney.Mechanistically,MFN2 preferably binded small GTPaseRab21 in its GTPloading form,which was colocalized with endocytosed EGFR in ccRCC cells.Through this EGFR-Rab21-MFN2 interaction,endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J(PTPRJ).Conclusions:Our findings uncover an important non-canonicalmitochondriadependent pathway regulating EGFR signaling by the Rab21-MFN2-PTPRJ axis,which contributes to the development of novel therapeutic strategies for ccRCC.

The Role of Soft Vein Joints in Dragonfly Flight

Dragonflies are excellent flyers among insects and their flight ability is closely related to the architecture and material properties of their wings. The veins are main structure components of a dragonfly wing, which are found to be connected by resilin with high elasticity at some joints. A three-dimensional （3D） finite element model of dragonfly wing considering the soft vein joints is developed, with some simplifications. Passive deformation under aerodynamic loads and active flapping motion of the wing are both studied. The functions of soft vein joints in dragonfly flight are concluded. In passive deformation, the chordwise flexibility is improved by soft vein joints and the wing is cambered under loads, increasing the action area with air. In active flapping, the wing rigidity in spanwise direction is maintained to achieve the required amplitude. As a result, both the passive deformation and the active control of flapping work well in dragonfly flight. The present study may also inspire the design of biomimetic Flapping Micro Air Vehicles （FMAVs）.

Relative humidity and temperature dependence of mechanical degradation of natural fiber composites^(?)

In this paper,the mechanical degradation of natural fiber composites is studied with the consideration of the relative humidity and the temperature.A nonlinear constitutive model is established,which employs an internal variable to describe the mechanical degradation related to the energy dissipation during moisture absorption.The existing experimental researches demonstrated that the mechanical degradation is an irreversible thermodynamic process induced by the degradation of fibers and the damages of interfaces between fiber and matrix,both of which depend on the variation of the relative humidity or the temperature.The evolution of the mechanical degradation is obtained through the determination of dissipation rates as a function of the relative humidity and the temperature.The theoretically predicted mechanical degradations are compared with experimental results of sisal fiber reinforced composites subject to different relative humidity and temperatures,and a good agreement is found.