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DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling

ABSTRACT: Using stable cell lines, we found that succinylation levels were highly dependent on DLST. Furthermore, PPGL-causing DLST mutations, predicted to alter DLST homo-oligomeric complex structure, caused a significant remodeling of the cellular succinylome. Succinylation is thought to cause major chemical and structural changes in proteins, most likely influencing their function. Accordingly, we found that the dysregulation of succinylation appeared to influence several essential pathways related to PPGL development such as hypoxia, glycolysis and oxidative phosphorylation. This study points to succinylation as a new mechanism involved in the development of PPGLs, supporting the growing body of research highlighting the role of this PTM in different types of cancer.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Pheochromocytoma

SUBMITTER: Fernando Garcia

LAB HEAD: Fernando Garcia Martinez

PROVIDER: PXD036782 | Pride | 2023-05-04

REPOSITORIES: Pride

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			Action	DRS
	20200922_Sara_sucinyl_E02_S01_IP1_01.raw	Raw
	20200922_Sara_sucinyl_E02_S01_IP1_02.raw	Raw
	20200922_Sara_sucinyl_E02_S01_IP2_01.raw	Raw
	20200922_Sara_sucinyl_E02_S01_IP2_02.raw	Raw
	20200922_Sara_sucinyl_E02_S02_IP1_01.raw	Raw

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Project description:Background Hypothyroidism is a common disease, and its molecular mechanism still needs further investigation. Succinylation, as a newly identified protein posttranslational modification, is found to be involved in various metabolisms and cellular processes. In the present study, we performed quantitative analysis of the lysine succinylome in the thyroid of rats with hypothyroxinemia. Methods Hypothyroxinemia was induced in rats through the administration of a high-fat diet and then the thyroid tissues were taken out for further analysis. Affinity enrichment and liquid chromatography-tandem mass spectrometry techniques were applied for the quantitative proteome and succinylome analyses, respectively. Bioinformatic analyses were performed to decipher the differentially expressed proteins and succinylated sites, including the gene ontology (GO) annotation-based classification, Wolfpsort-based subcellular localization prediction, Kyoto Encyclopedia of Genes and Genomes (KEGG)-based functional pathway enrichment, and conserved domains of protein and succinylation sites prediction. Finally, the mitochondrial oxygen consumption rates of human normal thyroid epithelial cells were measured to further verify the role of lysine succinylation in vitro. Results Overall, 3869 proteins were identified, among which 129 differentially expressed proteins were quantified. Downregulated expressed proteins were enriched in the thyroid hormone synthesis and thyroid hormone signaling pathways and were mainly localized to the mitochondria and ATPase complex. In addition, 685 lysine succinylation sites on 250 proteins were identified, of which 172 lysine succinylation sites on 104 proteins were obvious changed (7 upregulated on 5 proteins and 165 downregulated on 99 proteins). Decreased succinylated proteins were involved in diverse metabolic pathways and biological processes, including the tricarboxylic acid cycle (TCA cycle), cellular respiration, energy derivation by oxidation of organic compounds and aerobic respiration. Moreover, these decreased succinylated proteins were primarily localized to the mitochondria. Finally, OCRs related to basal respiration, ATP production and maximal respiration were markedly blunted in the normal thyroid epithelial cells treated with palmitic acid (all p < 0.05), and the changes were reversed when the cells were treated with palmitic acid and desuccinylase inhibitor together (all p < 0.05). Conclusions The thyroid differentially expressed proteins and changed succinylation levels played a potential role in the mitochondria-mediated energy metabolism in the HFD-induced hypothyroxinemia rat model.

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DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling

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