Identification of elongation factor‐2 as a novel regulator of mitochondrial fission
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 unapprec...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley-VCH
2022-07-01
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| Series: | Natural Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ntls.20220011 |
| _version_ | 1811225626315587584 |
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| author | 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 Jin‐Ming Yang |
| author_facet | 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 Jin‐Ming Yang |
| author_sort | Jinhwan Kim |
| collection | DOAJ |
| description | 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 humans, 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, colocalized at the mitochondria, as evidenced by microscopic observation, coimmunoprecipitation, 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. Key Points We demonstrate that eEF‐2 localizes in the mitochondria, in addition to its presence in the cytosol. This study identifies eEF‐2 as a novel regulator of mitochondrial fission. This work uncovers the interaction of eEF‐2 with Drp1 and its effect on GTPase activity as a new mechanism that regulates mitochondrial dynamics. |
| first_indexed | 2024-04-12T09:10:32Z |
| format | Article |
| id | doaj.art-83d314c05ccf4e4cbfdb70cc8544a1fd |
| institution | Directory Open Access Journal |
| issn | 2698-6248 |
| language | English |
| last_indexed | 2024-04-12T09:10:32Z |
| publishDate | 2022-07-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | Natural Sciences |
| spelling | doaj.art-83d314c05ccf4e4cbfdb70cc8544a1fd2022-12-22T03:38:59ZengWiley-VCHNatural Sciences2698-62482022-07-0123n/an/a10.1002/ntls.20220011Identification of elongation factor‐2 as a novel regulator of mitochondrial fissionJinhwan Kim0Yanfeng Li1Yan Cheng2Xingcong Ren3Yi Zhang4Cheng Ji5Hua Zhu6Yoshinori Takahashi7Xingdong Xiong8Lixiang Gu9Chrispus Ngule10Xiaofang Xiong11Jianxun Song12Xiaoqi Liu13Jin‐Ming Yang14Department of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Surgery The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pediatrics College of Medicine and Milton S. Hershey Medical Center 500 University Drive The Pennsylvania State University Hershey Pennsylvania USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Microbial Pathogenesis and Immunology Texas A&M University Health Science Center Bryan Texas USADepartment of Microbial Pathogenesis and Immunology Texas A&M University Health Science Center Bryan Texas USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USADepartment of Toxicology and Cancer Biology, College of Medicine Markey Cancer Center University of Kentucky Lexington Kentucky USAAbstract 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 humans, 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, colocalized at the mitochondria, as evidenced by microscopic observation, coimmunoprecipitation, 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. Key Points We demonstrate that eEF‐2 localizes in the mitochondria, in addition to its presence in the cytosol. This study identifies eEF‐2 as a novel regulator of mitochondrial fission. This work uncovers the interaction of eEF‐2 with Drp1 and its effect on GTPase activity as a new mechanism that regulates mitochondrial dynamics.https://doi.org/10.1002/ntls.20220011Drp1dynamicseEF2fissionfusionmitochondria |
| spellingShingle | 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 Jin‐Ming Yang Identification of elongation factor‐2 as a novel regulator of mitochondrial fission Natural Sciences Drp1 dynamics eEF2 fission fusion mitochondria |
| title | Identification of elongation factor‐2 as a novel regulator of mitochondrial fission |
| title_full | Identification of elongation factor‐2 as a novel regulator of mitochondrial fission |
| title_fullStr | Identification of elongation factor‐2 as a novel regulator of mitochondrial fission |
| title_full_unstemmed | Identification of elongation factor‐2 as a novel regulator of mitochondrial fission |
| title_short | Identification of elongation factor‐2 as a novel regulator of mitochondrial fission |
| title_sort | identification of elongation factor 2 as a novel regulator of mitochondrial fission |
| topic | Drp1 dynamics eEF2 fission fusion mitochondria |
| url | https://doi.org/10.1002/ntls.20220011 |
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