1. Academic Validation
  2. SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma

  • Adv Sci (Weinh). 2023 Oct 30:e2303535. doi: 10.1002/advs.202303535.
Qifan Hu 1 2 3 Jing Xu 2 Lei Wang 2 Yi Yuan 4 Ruiguang Luo 2 Mingxi Gan 2 Keru Wang 4 Tao Zhao 2 Yawen Wang 2 Tianyu Han 3 5 6 Jian-Bin Wang 1 2
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 2 School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, 330031, China.
  • 3 Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 4 School of Huankui Academy, Nanchang University, Nanchang, Jiangxi, 330031, China.
  • 5 Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, 330006, China.
  • 6 China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang, Jiangxi, 330200, China.
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.

Keywords

SIRT5; SUCLG2; TRIM21; mitochondrial dysfunction; succinylation.

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