Aims: Ferroptosis, an iron-dependent non-apoptotic cell
death mechanism, profoundly impacts cellular metabolism. Despite its
significance, a comprehensive metabolomic analysis of ferroptotic cells remains
elusive.
Study Design and Methodology: In this study, we investigated the metabolome
of H9c2 cardioblast cells using gas chromatography-mass spectrometry during
ferroptosis induced by RSL3, an inhibitor of glutathione peroxidase 4. Notably,
we explored the effects of ferroptosis inhibitors, including ferrostatin-1, and
the mitochondrial-targeted ROS scavenger, XJB-5-131.
Place and Duration of Study: Department of Physiology and
Department of Biochemistry, University of Puerto Rico School of Medicine,
between October 2019 and September 2021.
Results: The results revealed a significant reduction of
amino acids crucial for glutathione synthesis by more than two-fold upon RSL3
treatment. Conversely, saturated fatty acid levels were notably elevated in
RSL3-exposed cells, with no discernible impact on unsaturated fatty acids.
Moreover, RSL3 induced substantial alterations in mitochondrial tricarboxylic
acid cycle intermediates; while isocitrate and 2-oxoglutarate levels increased,
succinate levels decreased significantly in RSL3-treated cells. Importantly,
ferrostatin-1 and XJB-5-131 effectively prevented RSL3-induced cell death and
preserved the metabolic profile. Given the involvement of 2-oxoglutarate in
ferroptosis regulation, particularly through glutamine metabolism, we further
investigated the role of glutaminolysis in H9c2 cardi-oblasts ferroptosis.
Silencing of glutaminase 1, encoding the K-type mitochondrial glutaminase
(glutaminase C), conferred protection against ferroptosis at the early stage.
Conclusion: In conclusion, our study demonstrates the
disruptive impact of RSL3-induced ferroptosis on the metabolome of H9c2
cardioblasts.
Author(s) Details:
Keishla M. Rodríguez-Graciani,
Department of Physiology, School of Medicine, University of Puerto
Rico, San Juan, PR, USA.
Xavier R.
Chapa-Dubocq,
Department
of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR,
USA.
Esteban J. Ayala-Arroyo,
Department of Physiology, School of Medicine, University of Puerto
Rico, San Juan, PR, USA.
Ivana Chaves-Negrón,
Department of Physiology, School of Medicine, University of Puerto
Rico, San Juan, PR, USA.
Sehwan Jang,
Department of Physiology, School of Medicine, University of Puerto
Rico, San Juan, PR, USA.
Nataliya Chorna,
Department
of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, PR,
USA.
Taber S. Maskrey,
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA,
USA.
Peter Wipf,
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA,
USA.
Sabzali Javadov,
Department of Physiology, School of Medicine, University of Puerto Rico, San
Juan, PR, USA.
Please see the link here: https://stm.bookpi.org/NVMMS-V5/article/view/14153
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