Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver

Bychkova, Solomiia; Bychkov, Mykola; Dordevic, Dani; Vítězová, Monika; Rittmann, Simon K.-M. R.; Kushkevych, Ivan

doi:10.3390/ijms25031657

IJMS

2024

DOI: 10.3390/ijms25031657

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Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver

Solomiia Bychkova,

Mykola Bychkov,

Dani Dordevic

et al.

Abstract: Bafilomycin A1 inhibits V-type H+ ATPases on the molecular level, which acidifies endo-lysosomes. The main objective of the study was to assess the effect of bafilomycin A1 on Ca2+ content, NAADP-induced Ca2+ release, and ATPase activity in rat hepatocytes and human colon cancer samples. Chlortetracycline (CTC) was used for a quantitative measure of stored calcium in permeabilized rat hepatocytes. ATPase activity was determined by orthophosphate content released after ATP hydrolysis in subcellular post-mitocho… Show more

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Cited by 3 publications

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Energy metabolism, immune function, and intestinal flora in rats with kidney-yin deficiency treated with raw or saltwater-processed Phellodendron chinense Schneid

Ren,

Zhao,

et al. 2024

Journal of Traditional Chinese Medical Sciences

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Energy metabolism, immune function, and intestinal flora in rats with kidney-yin deficiency treated with raw or saltwater-processed Phellodendron chinense Schneid

Ren,

Zhao,

et al. 2024

Journal of Traditional Chinese Medical Sciences

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Dysregulation of protein degradation and alteration of secretome in α-synuclein-exposed astrocytes: implications for dopaminergic neuronal dysfunction

Raj,

Banerjee,

Holla

et al. 2024

Cell Commun Signal

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Background A key factor in the propagation of α-synuclein pathology is the compromised protein quality control system. Variations in membrane association and astrocytic uptake between different α-synuclein forms suggest differences in exocytosis or membrane cleavage, potentially impacting the secretome's influence on dopaminergic neurons. We aimed to understand differences in protein degradation mechanisms of astrocytes for both wild-type (WT) and mutant forms of α-synuclein, specifically during periods of reduced degradation efficiency. We also investigated α-synuclein release into the secretome and its effects on healthy dopaminergic neurons. Methods Cellular models used were rat primary astrocytes alongside hiPSC-derived astrocytes, whose impact on rat primary dopaminergic neurons and the human SH-SY5Y cell line was investigated. We examined the release and accumulation of α-synuclein resulting from impaired degradatory pathways, including matrix metalloprotease-MMP9, the ubiquitin proteasomal pathway-UPS, and the autophagy-lysosomal pathway-ALP, using immunocytochemical analysis and flow cytometry. Additionally, we explored the effect of astrocytic secretome on dopaminergic-neuronal survival, neurite collapse and function. Results At early stages, astrocytes were able to deal efficiently with monomeric α-synuclein (via UPS), and larger aggregates (through MMP9 and autophagy), clearing extracellular α-synuclein and maintaining neuronal health. However, extended exposure to extracellular monomeric and aggregated α-synuclein compromised their proteasomal activity, inhibiting MMP9 and destabilizing autophagy, transforming astrocytes from protectors to promoters of neurodegeneration. This study is the first to elucidate the astrocytes' preferred degradation pathways for both monomeric and aggregated forms of α-synuclein, along with the subsequent effects of these payloads on the cellular degradation machinery. The astrocytic transformation is characterized by α-synuclein expulsion, increased release of inflammatory cytokines, and diminished secretion of growth factors leading to dopaminergic neuronal apoptosis and dysfunction, particularly neurite collapse, intracellular Ca 2+ response and vesicular dopamine release. The presence of phosphorylated and nitrated α-synuclein species in astrocytes also suggests their potential involvement in modifying both forms of the protein. Conclusion The initial protective action of astrocytes in clearing and degrading extracellular α-synuclein is severely compromised at latter stages, leading to astrocytic dysfunction and impairing neuron-glia cross-talk. This study underscores the criticality of integrating astrocytes into treatment paradigms in synucleinopathies. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-024-01928-9.

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The impact of 3-sulfo-taurolithocholic acid on ATPase activity in patients’ colorectal cancer and normal colon tissues, and its hepatic effects in rodents

Bychkova,

Bychkov,

Dordević

et al. 2024

Front. Vet. Sci.

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Colorectal cancer is influenced by genetic mutations, lifestyle factors, and diet, particularly high fat intake, which raises bile acid levels in the intestinal lumen. This study hypothesized that bile acids contribute to tumorigenesis by disrupting ion transport and ATPase activity in the intestinal mucosa. The effects of 3-sulfo-taurolithocholic acid (TLC–S) on ATPase activity were investigated in colorectal cancer samples from 10 patients, using adjacent healthy tissue as controls, and in rodent liver function. ATPase activity was measured spectrophotometrically by determining inorganic phosphorus (Pi) in postmitochondrial fractions. Ca2+ dynamics were assessed in isolated mouse hepatocytes with fluorescence imaging, and rat liver mitochondria were studied using polarographic methods to evaluate respiration and oxidative phosphorylation. TLC–S increased Na+/K+ ATPase activity by 1.5 times in colorectal cancer samples compared to controls (p ≤ 0.05). In healthy mucosa, TLC–S decreased Mg2+ ATPase activity by 3.6 times (p ≤ 0.05), while Mg2+ ATPase activity in cancer tissue remained unchanged. TLC–S had no significant effect on Ca2+ ATPase activity in healthy colon mucosa but showed a trend toward decreased activity in cancer tissue. In rat liver, TLC–S decreased Ca2+ ATPase and Na+/K+ ATPase activities while increasing basal Mg2+ ATPase activity (p ≤ 0.05). Additionally, TLC–S induced cytosolic Ca2+ signals in mouse hepatocytes, partially attenuated by NED-19, an NAADP antagonist (p ≤ 0.05). TLC–S also reduced the V3 respiration rate of isolated rat liver mitochondria during α-ketoglutarate oxidation. These findings suggest that TLC–S modulates ATPase activity differently in cancerous and healthy colon tissues, playing a role in colorectal cancer development. In rat liver, TLC–S affects mitochondrial activity and ATPase function, contributing to altered cytosolic calcium levels, providing insight into the mechanistic effects of bile acids on colorectal cancer and liver function.

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Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver

Cited by 3 publications

References 59 publications

Energy metabolism, immune function, and intestinal flora in rats with kidney-yin deficiency treated with raw or saltwater-processed Phellodendron chinense Schneid

Energy metabolism, immune function, and intestinal flora in rats with kidney-yin deficiency treated with raw or saltwater-processed Phellodendron chinense Schneid

Dysregulation of protein degradation and alteration of secretome in α-synuclein-exposed astrocytes: implications for dopaminergic neuronal dysfunction

The impact of 3-sulfo-taurolithocholic acid on ATPase activity in patients’ colorectal cancer and normal colon tissues, and its hepatic effects in rodents

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