Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers

Trisolini, Lucia; Laera, Luna; Favia, Maria; Muscella, Antonella; Castegna, Alessandra; Pesce, Vito; Guerra, Lorenzo; Grassi, Anna; Volpicella, Mariateresa; Pierri, Ciro Leonardo

doi:10.3390/biom11010038

Cited by 14 publications

(9 citation statements)

References 86 publications

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“…These inhibit KIR6.1/2-SUR protein complexes with high specificity at the corresponding ATP binding regions, with ATP isopentenyl ester being found to also inhibit ADP/ATP carrier [ 51 ]. This has important implications for mitochondrial function and ADP/ATP carrier mediated mitochondrial apoptosis triggering [ 52 , 53 ]. This could represent an additional ZOL-mediated indirect mechanism of blocking KATP channels.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions

et al. 2021

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Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows similarities with nucleotides, ligands of ATP-sensitive K+ (KATP) channels. We investigated the action of ZOL by performing in vitro patch-clamp experiments on native KATP channels in murine skeletal muscle fibers, bone cells, and recombinant subunits in cell lines, and by in silico docking the nucleotide site on KIR and SUR, as well as the glibenclamide site. ZOL fully inhibited the KATP currents recorded in excised macro-patches from Extensor digitorum longus (EDL) and Soleus (SOL) muscle fibers with an IC50 of 1.2 ± 1.4 × 10−6 and 2.1 ± 3.7 × 10−10 M, respectively, and the KATP currents recorded in cell-attached patches from primary long bone cells with an IC50 of 1.6 ± 2.8 × 10−10 M. ZOL fully inhibited a whole-cell KATP channel current of recombinant KIR6.1-SUR2B and KIR6.2-SUR2A subunits expressed in HEK293 cells with an IC50 of 3.9 ± 2.7 × 10−10 M and 7.1 ± 3.1 × 10−6 M, respectively. The rank order of potency in inhibiting the KATP currents was: KIR6.1-SUR2B/SOL-KATP/osteoblast-KATP > KIR6.2-SUR2A/EDL-KATP >>> KIR6.2-SUR1 and KIR6.1-SUR1. Docking investigation revealed that the drug binds to the ADP/ATP sites on KIR6.1/2 and SUR2A/B and on the sulfonylureas site showing low binding energy <6 Kcal/mol for the KIR6.1/2-SUR2 subunits vs. the <4 Kcal/mol for the KIR6.2-SUR1. The IC50 of ZOL to inhibit the KIR6.1/2-SUR2A/B channels were correlated with its musculoskeletal and cardiovascular risks. We first showed that ZOL blocks at subnanomolar concentration musculoskeletal KATP channels and cardiac and vascular KIR6.2/1-SUR2 channels.

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Section: Discussionmentioning

confidence: 99%

Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions

et al. 2021

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“…The genes forming the detected module point to an interesting biological ATP protein complex. ATP proteins are mitochondrial transport proteins and were recently verified as potential biomarker for kidney survival prognosis 50 . In addition to that, we report on a special importance of the ATP6V1C2 protein for survival prediction (see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We see about 10–15% of the best-ranked elements highlighted across the various explanations, which we believe indicates a high performance of the feature selection process. Node importance explanation allows aggregating information over multi-omics data—ATP6V1C2 50 , BIRC5 51 , and CCNB1 52 appear as most important (Fig. 7 , left panel).…”

Section: Resultsmentioning

confidence: 99%

Multi-omics disease module detection with an explainable Greedy Decision Forest

Pfeifer

Baniecki

Saranti

et al. 2022

Sci Rep

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Machine learning methods can detect complex relationships between variables, but usually do not exploit domain knowledge. This is a limitation because in many scientific disciplines, such as systems biology, domain knowledge is available in the form of graphs or networks, and its use can improve model performance. We need network-based algorithms that are versatile and applicable in many research areas. In this work, we demonstrate subnetwork detection based on multi-modal node features using a novel Greedy Decision Forest (GDF) with inherent interpretability. The latter will be a crucial factor to retain experts and gain their trust in such algorithms. To demonstrate a concrete application example, we focus on bioinformatics, systems biology and particularly biomedicine, but the presented methodology is applicable in many other domains as well. Systems biology is a good example of a field in which statistical data-driven machine learning enables the analysis of large amounts of multi-modal biomedical data. This is important to reach the future goal of precision medicine, where the complexity of patients is modeled on a system level to best tailor medical decisions, health practices and therapies to the individual patient. Our proposed explainable approach can help to uncover disease-causing network modules from multi-omics data to better understand complex diseases such as cancer.

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“…The mitochondrial oxidative phosphorylation (OXPHOS) process plays a pivotal role in cellular energy production by coupling the respiratory chain electron transfer to oxygen with the production of ATP. These organelles are also involved in various cellular metabolic pathways and play a critical role in apoptosis in phylogenetically distant eukaryotic organisms [ 1 , 2 , 3 , 4 , 5 ]. Thus, mitochondrial dysfunction may adversely affect cell physiology, and the abilities of mitochondria to provide the cell with the proper amount of ATP and to make correct life-or-death decisions are vital for supporting a healthy life.…”

Section: Introductionmentioning

confidence: 99%

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs

et al. 2022

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Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy.

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Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers

Cited by 14 publications

References 86 publications

Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions

Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions

Multi-omics disease module detection with an explainable Greedy Decision Forest

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs

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