Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 69, Issue -, Pages 229-238Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.01.031
Keywords
Redox; Thiol; Extracellular flux analysis; Nitric oxide; Nitrosylation; Free radicals
Funding
- Redox Biology Program at the Medical College of Wisconsin
- Wisconsin Breast Cancer Showhouse
- Interdisciplinary Cancer Research Post-Doctoral Fellowship from the Cancer Center of the Medical College of Wisconsin
- National Institutes of Health Grant [R01-GM-55792]
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Energy substrates metabolized through mitochondria (e.g., pyruvate, glutamine) are required for biosynthesis of macromolecules in proliferating cells. Because several mitochondrial proteins are known to be targets of S-nitrosation, we determined whether bioenergetics are modulated by S-nitrosation and defined the subsequent effects on proliferation. The nitrosating agent S-nitroso-L-cysteine (L-CysNO) was used to initiate intracellular S-nitrosation, and treatment decreased mitochondrial function and inhibited proliferation of MCF7 mammary adenocarcinoma cells. Surprisingly, the D-isomer of CysNO (D-CysNO), which is not transported into cells, also caused mitochondrial dysfunction and limited proliferation. Both L- and D-CysNO also inhibited cellular pyruvate uptake and caused S-nitrosation of thiol groups on monocarboxylate transporter 1, a proton-linked pyruvate transporter. These data demonstrate the importance of mitochondrial metabolism in proliferative responses in breast cancer and highlight a novel role for inhibition of metabolic substrate uptake through S-nitrosation of exofacial protein thiols in cellular responses to nitrosative stress. (c) 2014 Elsevier Inc. All rights reserved.
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