Biology subjects

Nesterenko, A. M.

Publications and source records attributed to Nesterenko, A. M..

4 recordsLinked to original sources

bioRxiv2024

Thermal Proteome Profiling reveals rapid proteomic responses to redox changes in specific cellular compartments

Hydrogen peroxide (H2O2) functions as a secondary messenger in cellular redox signaling, acting mainly via oxidation of protein thiols. Its spatially and temporally regulated activity within cells is essential for maintaining proper redox balance, and disruptions in these patterns can lead to oxidative stress and various related pathologies. Redox proteomics, which examines the impact of H2O2 at the proteome level, typically focuses only on thiol oxidation, overlooking broader proteomic alterations and the significance of subcellular localization in these redox processes. In this study, we address these open questions by combining chemogenetics with Thermal Proteome Profiling (TPP) to map global proteome response to compartmentalized H2O2 production. We identified hundreds of proteins with altered thermostability and/or abundance upon localized H2O2 generation in the cytosol, nucleus, and the ER lumen, highlighting their roles in cellular responses to localized H2O2. We identified proteins such as MAP2K1, PARK7, TRAP1, and UBA2 to be highly sensitive to localized H2O2 production. Furthermore, we validated their altered thermostability and found that these changes are controlled via dysregulated protein-protein interactions. This study provides a valuable resource for researchers exploring redox-mediated signal transduction and offers novel insights that could be harnessed in treating oxidative stress-induced pathologies.

systems biology↗

bioRxiv2024

Thermogenetics for cardiac pacing

Cardiac arrhythmias are common disorders that can be fatal. Modern methods of treating bradyarrhythmias include the implantation of pacemakers and cardioverter-defibrillators. However, implantable devices can cause various complications related to the electrodes installed inside the heart, including infection. Less invasive heart rhythm modulation could be beneficial for some cohorts of patients. Here, we demonstrate an alternative approach to heart pacing based on thermogenetics. We used adeno-associated viruses to deliver genetic human transient receptor potential subfamily V member 1 (TRPV1), a heat-sensitive cation channel, into isolated cardiomyocytes and the mouse heart. This allowed us to induce action potentials and control contractility using short heat pulses delivered by infrared laser illumination. Using this approach, we demonstrated the thermogenetic pacing of isolated cardiomyocytes in vitro and in the mouse heart in vivo. Our results demonstrate the potential of thermogenetics for developing therapeutic strategies for heart rhythm modulation.

synthetic biology↗

bioRxiv2023

Grubraw, a chemogenetic generator of mitochondrial pyruvate, reveals new mechanisms of mitochondrial metabolic control that underlie the Warburg effect

Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, are characteristic of tumor cells1,2. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon3. Warburg-type metabolism is beneficial for rapidly proliferating cells, however its function remains unclear. Moreover, it is unknown what the metabolic consequences of activation of mitochondrial respiration in Warburg-type cancer cells are. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate directly in the mitochondrial matrix bypassing restricted pyruvate influx. In cancer cells, Grubraw-driven pyruvate synthesis in the matrix increased mitochondrial membrane potential, oxygen consumption rate, and the amounts of TCA cycle intermediates. In a mouse model of human melanoma xenografts, chemogenetic activation of mitochondria caused a decrease in tumor growth rate. Surprisingly, cancer cells actively exported pyruvate generated by Grubraw in the mitochondria into the extracellular medium. In addition, activation of mitochondria induced downregulation of transcription of the genes that drive cell cycle progression, cell proliferation and DNA replication. Our results demonstrate that cells with Warburg-type metabolism use previously unknown mechanisms of carbon flux control to dispose of excessive mitochondrial pyruvate, and activation of mitochondria in these cells downregulates cellular proliferation.

cancer biology↗

bioRxiv2018

Bioinformatic screening of genes present only in well regenerating vertebrates reveals novel FGF and purinergic signaling modulator - c-Answer

The genetic basis of higher regenerative capacity of fishes, amphibians and reptiles compared to birds and mammals is still poorly understood. Though it is thought to be a result of restructuring in the regulatory network of a static set of genes, we argued that it could be due to the loss of genes essential for regeneration. In the present work, we formulate a bioinformatic approach to systematic search for the such genes. Having identified them, we further investigated one we dubbed \"c-Answer\", which encodes a membrane protein, regulating the regeneration of body appendages and the telencephalic development through binding to FGFR and P2Y1 receptors and promoting MAPK/ERK and purinergic signaling. The obtained data suggest that elimination of c-Answer in the ancestors of warm-blooded animals conditioned the decreased activity of at least two signaling pathways, which in turn could contribute to changes in mechanisms that regulate the forebrain development and regeneration.

developmental biology↗