In demyelinating nervous system disorders, myelin basic protein (MBP), a major component of the myelin sheath, is proteolyzed and its fragments are released in the neural environment. Here, we demonstrated that, in contrast with MBP, the cellular uptake of the cryptic 84–104 epitope (MBP84-104) did not involve the low-density lipoprotein receptor-related protein-1, a scavenger receptor. Our pull-down assay, mass spectrometry and molecular modeling studies suggested that, similar with many other unfolded and aberrant proteins and peptides, the internalized MBP84-104 was capable of binding to the voltage-dependent anion-selective channel-1 (VDAC-1), a mitochondrial porin. Molecular modeling suggested that MBP84-104 directly binds to the N-terminal α-helix located midway inside the 19 β-blade barrel of VDAC-1. These interactions may have affected the mitochondrial functions and energy metabolism in multiple cell types. Notably, MBP84-104 caused neither cell apoptosis nor affected the total cellular ATP levels, but repressed the aerobic glycolysis (lactic acid fermentation) and decreased the l-lactate/d-glucose ratio (also termed as the Warburg effect) in normal and cancer cells. Overall, our findings implied that because of its interactions with VDAC-1, the cryptic MBP84-104 peptide invoked reprogramming of the cellular energy metabolism that favored enhanced cellular activity, rather than apoptotic cell death. We concluded that the released MBP84-104 peptide, internalized by the cells, contributes to the reprogramming of the energy-generating pathways in multiple cell types.
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July 2018
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The transfer of mitochondria between mesenchymal stem cells (MSCs) (red) and glioblastoma stem cells (GSCs) (green). In the zoomed inset, MSC mitochondria (labelled with asterisks) can be seen inside a GSC; for details, see pages 2305–2328.
Research Article|
July 31 2018
Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism
Albert G. Remacle;
Albert G. Remacle
1Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
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Swathi K. Hullugundi;
Swathi K. Hullugundi
2Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, U.S.A.
3VA San Diego Healthcare System, La Jolla, CA 92037, U.S.A.
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Jennifer Dolkas;
Jennifer Dolkas
2Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, U.S.A.
3VA San Diego Healthcare System, La Jolla, CA 92037, U.S.A.
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Mila Angert;
Mila Angert
2Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, U.S.A.
3VA San Diego Healthcare System, La Jolla, CA 92037, U.S.A.
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Piotr Cieplak;
Piotr Cieplak
1Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
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David Scott;
David Scott
1Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
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Andrei V. Chernov;
Andrei V. Chernov
1Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
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Veronica I. Shubayev;
Veronica I. Shubayev
2Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, U.S.A.
3VA San Diego Healthcare System, La Jolla, CA 92037, U.S.A.
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Alex Y. Strongin
1Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
Correspondence: Alex Y. Strongin (strongin@SBPdiscovery.org)
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Publisher: Portland Press Ltd
Received:
February 14 2018
Revision Received:
June 20 2018
Accepted:
June 28 2018
Accepted Manuscript online:
June 28 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (14): 2355–2376.
Article history
Received:
February 14 2018
Revision Received:
June 20 2018
Accepted:
June 28 2018
Accepted Manuscript online:
June 28 2018
Citation
Albert G. Remacle, Swathi K. Hullugundi, Jennifer Dolkas, Mila Angert, Piotr Cieplak, David Scott, Andrei V. Chernov, Veronica I. Shubayev, Alex Y. Strongin; Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism. Biochem J 31 July 2018; 475 (14): 2355–2376. doi: https://doi.org/10.1042/BCJ20180137
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