Journal Article

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma

Xu, Jing, Han, Tianyu, Wang, Jian‐Bin, Luo, Ruiguang, Hu, Qifan, Wang, Keru, Yuan, Yi, Wang, Lei, Zhao, Tao, Gan, Mingxi, Wang, Yawen

2023

Overview

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. In LUAD, succinylation on Lys93 increases SUCLG2 stability, leading to metabolic reprogramming and tumor progression. SIRT5 desuccinylates SUCLG2 on Lys93, followed by TRIM21‐mediated ubiquitination through K63‐linkage and degradation in the lysosome, this leads to the upregulation of succinyl‐CoA and protein succinylation in the mitochondria and inhibits mitochondrial function. This study discovers a new function for SUCLG2 in tumor progression.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenocarcinoma of Lung - metabolism / Cell growth / Enzymes / Humans / Kinases / Lung cancer / Metabolism / Mitochondria - metabolism / Mitochondrial Diseases - metabolism / Mitochondrial DNA / mitochondrial dysfunction / Prostate cancer / Protein expression / Proteins / SIRT5 / Statistical analysis / succinylation / SUCLG2 / TRIM21 / Tumors