Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.celrep.2023.112041 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeted Next-Generation Sequencing in Succinate Dehydrogenase-Deficient GI Stromal Tumor Identifies Actionable Alterations in the PI3K/mTOR Pathway.
JCO Precis Oncol
January 2025
Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Purpose: Less than 5% of GI stromal tumors (GISTs) are driven by the loss of the succinate dehydrogenase (SDH) complex, resulting in a pervasive DNA hypermethylation pattern that leads to unique clinical features. Advanced SDH-deficient GISTs are usually treated with the same therapies targeting KIT and PDGFRA receptors as those used in metastatic GIST. However, these treatments display less activity in the absence of alternative therapeutic options.
View Article and Find Full Text PDFInfluence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.
Metabolites
December 2024
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya St., 3, Pushchino 142290, Russia.
Background: Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown.
View Article and Find Full Text PDFSimilar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.
Cancer Metab
December 2024
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 200 First St. SW, Rochester, MN, 55905, USA.
Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation.
View Article and Find Full Text PDFRenal cell carcinoma with succinate dehydrogenase A mutation: A case report and literature review.
Oncol Lett
February 2025
Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, P.R. China.
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of RCC characterized by the presence of a germline mutation in one of the four subunits of the SDH enzyme complex (SDHA, SDHB, SDHC and SDHD). Together with a somatic second hit, these variants lead to the loss of function of the SDH complex. SDH-deficient RCC associated with SDHA mutation is a rare condition; to the best of our knowledge, there have been only four patients reported in the literature.
View Article and Find Full Text PDFPGC-1α Promotes mitochondrial biosynthesis and energy metabolism of goose fatty liver.
Poult Sci
December 2024
College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China. Electronic address:
To investigate the functions of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the goose fatty liver, a total of 30 healthy 63-day-old male Landes geese were selected and randomly assigned to control group and overfeeding group. The overexpression or RNA interference assay of PGC-1α was performed in goose primary hepatocytes. Our data showed that the PGC-1α expression was increased in fatty liver.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!