SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma
Abstract Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl‐coenzyme A (CoA) synthet...
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202303535 |
| _version_ | 1827582882205401088 |
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| author | Qifan Hu Jing Xu Lei Wang Yi Yuan Ruiguang Luo Mingxi Gan Keru Wang Tao Zhao Yawen Wang Tianyu Han Jian‐Bin Wang |
| author_facet | Qifan Hu Jing Xu Lei Wang Yi Yuan Ruiguang Luo Mingxi Gan Keru Wang Tao Zhao Yawen Wang Tianyu Han Jian‐Bin Wang |
| author_sort | Qifan Hu |
| collection | DOAJ |
| description | Abstract Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl‐coenzyme A (CoA) synthetase GDP‐forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mitochondrial proteins and inhibits the function of key metabolic enzymes by reducing either enzymatic activity or protein stability, thus dampening mitochondrial function in LUAD cells. Interestingly, SUCLG2 itself is also succinylated on Lys93, and this succinylation enhances its protein stability, leading to the upregulation of SUCLG2 and promoting the proliferation and tumorigenesis of LUAD cells. Sirtuin 5 (SIRT5) desuccinylates SUCLG2 on Lys93, followed by tripartite motif‐containing protein 21 (TRIM21)‐mediated ubiquitination through K63‐linkage and degradation in the lysosome. The findings reveal a new role for SUCLG2 in mitochondrial dysfunction and clarify the mechanism of the succinylation‐mediated protein homeostasis of SUCLG2 in LUAD, thus providing a theoretical basis for developing anti‐cancer drugs targeting SUCLG2. |
| first_indexed | 2024-03-08T22:58:58Z |
| format | Article |
| id | doaj.art-db48a8b870064eb8be6715ec5b23d92a |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T22:58:58Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-db48a8b870064eb8be6715ec5b23d92a2023-12-16T04:16:14ZengWileyAdvanced Science2198-38442023-12-011035n/an/a10.1002/advs.202303535SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung AdenocarcinomaQifan Hu0Jing Xu1Lei Wang2Yi Yuan3Ruiguang Luo4Mingxi Gan5Keru Wang6Tao Zhao7Yawen Wang8Tianyu Han9Jian‐Bin Wang10Department of Thoracic Surgery The First Affiliated Hospital of Nanchang University Nanchang Jiangxi 330006 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Huankui Academy Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Huankui Academy Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaSchool of Basic Medical Sciences Nanchang University Nanchang Jiangxi 330031 ChinaJiangxi Institute of Respiratory Disease The First Affiliated Hospital of Nanchang University Nanchang Jiangxi 330006 ChinaDepartment of Thoracic Surgery The First Affiliated Hospital of Nanchang University Nanchang Jiangxi 330006 ChinaAbstract Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl‐coenzyme A (CoA) synthetase GDP‐forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mitochondrial proteins and inhibits the function of key metabolic enzymes by reducing either enzymatic activity or protein stability, thus dampening mitochondrial function in LUAD cells. Interestingly, SUCLG2 itself is also succinylated on Lys93, and this succinylation enhances its protein stability, leading to the upregulation of SUCLG2 and promoting the proliferation and tumorigenesis of LUAD cells. Sirtuin 5 (SIRT5) desuccinylates SUCLG2 on Lys93, followed by tripartite motif‐containing protein 21 (TRIM21)‐mediated ubiquitination through K63‐linkage and degradation in the lysosome. The findings reveal a new role for SUCLG2 in mitochondrial dysfunction and clarify the mechanism of the succinylation‐mediated protein homeostasis of SUCLG2 in LUAD, thus providing a theoretical basis for developing anti‐cancer drugs targeting SUCLG2.https://doi.org/10.1002/advs.202303535mitochondrial dysfunctionSIRT5succinylationSUCLG2TRIM21 |
| spellingShingle | Qifan Hu Jing Xu Lei Wang Yi Yuan Ruiguang Luo Mingxi Gan Keru Wang Tao Zhao Yawen Wang Tianyu Han Jian‐Bin Wang SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma Advanced Science mitochondrial dysfunction SIRT5 succinylation SUCLG2 TRIM21 |
| title | SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma |
| title_full | SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma |
| title_fullStr | SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma |
| title_full_unstemmed | SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma |
| title_short | SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma |
| title_sort | suclg2 regulates mitochondrial dysfunction through succinylation in lung adenocarcinoma |
| topic | mitochondrial dysfunction SIRT5 succinylation SUCLG2 TRIM21 |
| url | https://doi.org/10.1002/advs.202303535 |
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