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Cardiac Lysine Succinylome Profiling of Wild-Type and SIRT5-Deficient Mice at 4 Months after Irradiation

ABSTRACT: This study aimed to investigate the role of SIRT5 in regulating the cardiac succinylome following radiation exposure. The experiment utilized a cohort of six mice, comprising three SIRT5-knockout (SIRT5-KO) and three wild-type (WT) mice. All subjects received a single dose of thoracic radiation. Four months post-irradiation, cardiac tissues were collected. Quantitative proteomic analysis of succinylation modifications was then performed. Specifically, proteins were extracted from the heart tissues, digested with trypsin, and the resulting peptides were subjected to immunoaffinity enrichment using a high-specificity anti-succinyllysine antibody. The enriched succinylated peptides were analyzed using a timsTOF mass spectrometer coupled with nano-liquid chromatography in a 4D-data-independent acquisition (4D-FastDIA) mode. This advanced method provided high-depth, quantitative profiling of succinylation sites. The raw data were processed to identify and quantify lysine succinylation sites, enabling a comparative

ORGANISM(S): Mus Musculus

SUBMITTER: Anwen Liu

PROVIDER: PXD080310 | iProX | Mon Jun 29 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Objectives: To explore how modulation of cardiomyocyte SIRT5 levels affects the development of pathological cardiac remodeling and dysfunction. Background: SIRT5 is a mitochondrial NAD+-dependent deacylase, which regulates metabolic enzymes upon desuccinylation, demalonylation, and deglutarylation. Its role in the development of heart failure is not completely understood. Methods: Mice with cardiomyocyte-specific Sirt5 deletion (Sirt5-/-) or Sirt5 overexpression (cSirt5-Tg) underwent transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography and quantification of myocardial fibrosis and cardiomyocyte cell size. Metabolomic analysis and RNA sequencing were performed to identify potential novel pathways regulated by SIRT5. Results: While cardiac structure and function were similar in cSirt5-Tg compared to control mice, cSirt5-/- mice displayed exacerbated cardiac dilation, dysfunction, and fibrosis following TAC. Accumulation of metabolites involved in purine metabolism, particularly inosine and hypoxanthine, and reductions in nucleosides, adenosine and adenine, and nucleotides, AMP and ADP, were observed in hearts of cSirt5-/- mice and following TAC. Moreover, transcriptional analysis revealed upregulation of purine-nucleoside phosphorylase (PNP) and 5' nucleotidase, ecto (NT5E) and downregulation of adenosine kinase (ADK), which is likely to contribute to enhanced degradation of purine nucleotides and resulting accumulation of inosine and hypoxanthine in hearts of cSirt5-/- mice following TAC. Lastly, reduced SIRT5 expression and protein succinylation in left-ventricular tissue of patients with heart failure correlates with reduced ADK expression. Conclusions: Loss of SIRT5 aggravates cardiac remodeling and dysfunction in response to chronic pressure-overload possibly by dysregulation of genes involved in purine and pyrimidine metabolism, resulting in impaired ATP regeneration from adenosine.

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Cardiac Lysine Succinylome Profiling of Wild-Type and SIRT5-Deficient Mice at 4 Months after Irradiation

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