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.