Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis

Duarte, I. F.; Caio, João M.; Moedas, Marco F.; Rodrigues, Lénia; Leandro, Paula; Rivera, Isabel; Silva, Margarida F. B.

doi:10.1007/s00018-021-03996-3

Cited by 17 publications

(7 citation statements)

References 167 publications

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“…This multifaceted effect, revealed by our integrated pathway analysis, manifests as a signi cant downregulation of lysine degradation in cardiac cells. This combined pathway analysis unveils an accumulation of lysine and its precursor, L-α-aminoadipate, coupled with a signi cant suppression of dihydrolipoamide dehydrogenase, a critical pyruvate dehydrogenase complex subunit vital for β-oxidation and pyruvate-to-acetyl-CoA conversion feeding the TCA cycle (Duarte et al, 2021). Additionally, consistent with the lysine degradation pathway, TZD treatment associates with depleted carnitine and its precursor, γ-butyrobetaine.…”

Section: Decoding the Metabolic Remodeling Of Ac16mentioning

confidence: 66%

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Sultan,

Rattray,

Rattray

2024

Preprint

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Introduction Despite the well-established efficacy of thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, in type II diabetes management, their potential contribution to heart failure risk remains a significant area of uncertainty. This incomplete understanding, which persists despite decades of clinical use of TZDs, has generated ongoing controversy and unanswered questions regarding their safety profiles, ultimately limiting their broader clinical application. Objective and Methods This study presented a multi-omics approach, integrating toxicoproteomics and toxicometabolomics data with the goal of uncovering novel mechanistic insights into TZD cardiotoxicity and identifying molecular signatures predictive of side effect progression. Results Network analysis of proteo-metabolomic data revealed a distinct fingerprint of disrupted biochemical pathways, which were primarily related to energy metabolism. Downregulation of oxidative phosphorylation and fatty acid synthesis was coupled with increased activity in anaerobic glycolysis, the pentose phosphate pathway, and amino acid and purine metabolism. This suggests a potential metabolic shift in AC16 cells from fatty acid oxidation towards anaerobic glycolysis, potentially contributing to observed cardiotoxicity. Additionally, the study identified a marked disruption in the glutathione system, indicating an imbalanced redox state triggered by TZD exposure. Importantly, our analysis identified key molecular signatures across omics datasets, including prominent signatures of amino acids like L-ornithine, L-tyrosine and glutamine, which are established heart failure biomarkers, supporting their potential use for the early prediction of cardiotoxicity progression. Conclusion By uncovering a novel mechanistic explanation for TZD cardiotoxicity, this study simultaneously illuminates potential therapeutic interventions, opening avenues for future research to improve the safety profile of TZD agents.

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Section: Decoding the Metabolic Remodeling Of Ac16mentioning

confidence: 66%

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Sultan,

Rattray,

Rattray

2024

Preprint

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“…In line with the positive correlation observed between SLC31A1 and M2 macrophages, high expression of MTF1 is significantly associated with an increased infiltration of M2 macrophages, suggesting that MTF1 may exert anti-inflammatory effects in S. aureus -infected osteomyelitis by activating M2 macrophages. DLD, an essential gene involved in cellular copper death and the decarboxylation of pyruvate, 58 is linked to cell apoptosis and the generation of reactive oxygen species, making it relevant in the production of anticancer agents. As a positive regulator of cuproptosis, DLD promotes copper-dependent cell death.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Gene Analysis Reveals Cuproptosis-Related Gene Signature Associated with M2 Macrophage in Staphylococcus aureus-Infected Osteomyelitis

Shi,

Ni,

Tang

et al. 2024

JIR

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Objective Osteomyelitis is a challenging disease in the field of bone infections, with its immune and molecular regulatory mechanisms still poorly understood. The aim of this study is to explore the value and potential mechanisms of cuproptosis-related genes (CRGs) in Staphylococcus aureus ( S. aureus )-infected osteomyelitis from an immunological perspective. Methods Initially, three transcriptomic datasets from public databases were integrated and analyzed, and consistent expression of CRGs in S. aureus -infected osteomyelitis was identified. Subsequently, immune infiltration analysis was performed, and M2 macrophage-related CRGs (M2R-CRGs) were further identified. Their potential molecular mechanisms were evaluated using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA). Finally, distinct osteomyelitis subtypes and diagnostic models based on characteristic M2R-CRGs were constructed. Results Through correlation analysis with immune cell infiltration, three characteristic M2R-CRGs (SLC31A1, DLD, and MTF1) were identified. Further analysis using unsupervised clustering and immune microenvironment analysis indicated that cluster 1 might activate pro-inflammatory responses, while cluster 2 was shown to exhibit anti-inflammatory effects in osteomyelitis. Compared to Cluster A, Cluster B demonstrated higher levels and a greater diversity of immune cell infiltrations in CRG-related molecular patterns, suggesting a potential anti-inflammatory role in osteomyelitis. A diagnostic model for S. aureus -infected osteomyelitis, based on the three M2R-CRGs, was constructed, exhibiting excellent diagnostic performance and validated with an independent dataset. Significant upregulation in mRNA and protein expression levels of the three M2R-CRGs was observed in rat models of S. aureus -infected osteomyelitis, aligning with bioinformatic results. Conclusion The M2R-CRGs (SLC31A1, DLD, and MTF1) may be considered characteristic genes for early diagnosis and personalized immune therapy in patients with S. aureus -infected osteomyelitis.

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“…A novel form of cell death induced by intracellular copper has been demonstrated in a recent study, which has been termed ‘cuproptosis’ and has been previously shown to occur through affecting TCA cycle ( 1 ). Cuproptosis operates through the binding of copper to one of the lipoylated components (in particular, the pyruvate dehydrogenase complex) of the TCA cycle, and DLD is a key regulator of the TCA cycle ( 15 ). DLD has been reported to participate in a variety of cellular processes in humans, such as regulating energy metabolism and the cell cycle ( 16 – 18 ).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic role of copper‑induced cell death‑associated protein DLD in human cancer: A pan‑cancer analysis and experimental verification

Han

Zhu

2023

Oncol Lett

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Copper ions can bind directly to lipoylated components of the tricarboxylic acid (TCA) cycle, triggering the aggregation of mitochondrial lipoylated proteins and the destabilization of Fe-S cluster proteins, resulting in copper-dependent cell death. Dihydrolipoamide dehydrogenase (DLD) is a key protein of the TCA cycle and constitutes the E3 component of the α-ketoglutarate dehydrogenase complex, which is deeply interconnected with the mitochondrial electron transfer chain in the TCA cycle. Tumor cells demonstrate dependency on glutaminolysis fuelling to carry out the TCA cycle and essential biosynthetic processes supporting tumor growth. Therefore, DLD plays an important role in the tumor biological process. However, to the best of our knowledge, no pan-cancer analysis is currently available for DLD. Therefore, the present study first explored the DLD expression profile in 33 tumors in publicly available datasets, including TIMER2, GEPIA2, UALCAN, cBioPortal and STRING. TIMER2, GEPIA2 and UALCAN were used for exploring gene expression; survival prognosis was detected by GEPIA2; genetic alteration was analysed by cBioPortal; immune infiltration data was obtained from TIMER2; interacting proteins of DLD were detected by STRING. DLD was found to be highly expressed in colon, liver, lung, stomach, renal, corpus uteri endometrial and ovarian cancers compared with normal tissues, and its high expression was associated with poorer prognosis in ovarian cancer. To the best of our knowledge, the present study provided the first comprehensive pan-cancer analysis of the oncogenic role of DLD across different tumors types. As the expression of DLD in ovarian cancer was high, and high expression is associated with poor prognosis, experimental verification of DLD in ovarian cancer was conducted. In the present study, DLD expression was found to be high in the ovarian cancer OC3 cell line, compared with the normal ovarian epithelial IOSE80 cell line by reverse transcription-quantitative PCR analysis. After knockdown of DLD expression, it was found that DLD regulated metabolic pathways by suppressing the intracellular NAD + /NADH ratio, which then in turn suppressed tumor cell proliferation detected by MTT assay. In conclusion, the present pan-cancer analysis of DLD demonstrated that DLD expression was associated with the clinical prognosis, immune infiltration and tumor mutational burden in 33 tumor types, and experimental verification in ovarian cancer was conducted. These results may contribute to the understanding of the role of DLD in tumorigenesis.

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Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis

Cited by 17 publications

References 167 publications

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Comprehensive Gene Analysis Reveals Cuproptosis-Related Gene Signature Associated with M2 Macrophage in Staphylococcus aureus-Infected Osteomyelitis

Oncogenic role of copper‑induced cell death‑associated protein DLD in human cancer: A pan‑cancer analysis and experimental verification

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