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Identification of Elongation Factor-2 as a Novel Regulator of Mitochondrial Fission
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  • Jinhwan Kim,
  • Yanfeng Li,
  • Yan Cheng,
  • Xingcong Ren,
  • Yi Zhang,
  • Cheng Ji,
  • Hua Zhu,
  • Yoshinori Takahashi,
  • Xingdong Xiong,
  • Lixiang Gu,
  • Chrispus Ngule,
  • Xiaofang Xiong,
  • Jianxun Song,
  • Xiaoqi Liu,
  • Jinming Yang
Jinhwan Kim
University of Kentucky College of Medicine

Corresponding Author:jki378@uky.edu

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Yanfeng Li
University of Kentucky College of Medicine
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Yan Cheng
University of Kentucky College of Medicine
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Xingcong Ren
University of Kentucky College of Medicine
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Yi Zhang
University of Kentucky College of Medicine
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Cheng Ji
University of Kentucky College of Medicine
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Hua Zhu
The Ohio State University Wexner Medical Center
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Yoshinori Takahashi
Penn State Health Milton S Hershey Medical Center
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Xingdong Xiong
University of Kentucky College of Medicine
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Lixiang Gu
University of Kentucky College of Medicine
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Chrispus Ngule
University of Kentucky College of Medicine
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Xiaofang Xiong
Texas A&M University College of Medicine
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Jianxun Song
Texas A&M University College of Medicine
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Xiaoqi Liu
University of Kentucky
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Jinming Yang
University of Kentucky College of Medicine
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Abstract

Mitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G-protein superfamily member encoded by EEF2 gene in human, has long been appreciated as a promoter of the GTP-dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, co-localized at the mitochondria, as evidenced by microscopic observation, co-immunoprecipitation, and GST pulldown assay. Deletion of the GTP binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild-type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria-related diseases.
07 Mar 2022Submitted to Natural Sciences
11 Mar 2022Submission Checks Completed
11 Mar 2022Assigned to Editor
11 Mar 2022Reviewer(s) Assigned
12 Apr 2022Review(s) Completed, Editorial Evaluation Pending
12 Apr 2022Editorial Decision: Revise Minor
21 Apr 20221st Revision Received
22 Apr 2022Submission Checks Completed
22 Apr 2022Assigned to Editor
26 Apr 2022Review(s) Completed, Editorial Evaluation Pending
27 Apr 2022Editorial Decision: Accept
Jul 2022Published in Natural Sciences volume 2 issue 3. 10.1002/ntls.20220011