Modification of Permeability Transition Pore Arginine(s) by Phenylglyoxal Derivatives in Isolated Mitochondria and Mammalian Cells: Structure-Function Relationship of Arginine Ligands
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Abstract
Methylglyoxal and synthetic glyoxal derivatives react
covalently with arginine residue(s) on the mitochondrial
permeability transition pore (PTP). In this study,
we have investigated how the binding of a panel of synthetic
phenylglyoxal derivatives influences the opening
and closing of the PTP. Using both isolated mitochondria
and mammalian cells, we demonstrate that the resulting
arginine-phenylglyoxal adduct can lead to either
suppression or induction of permeability transition, depending
on the net charge and hydrogen bonding capacity
of the adduct. We report that phenylglyoxal derivatives
that possess a net negative charge and/or are
capable of forming hydrogen bonds induced permeability
transition. Derivatives that were overall electroneutral
and cannot form hydrogen bonds suppressed permeability
transition. When mammalian cells were
incubated with low concentrations of negatively
charged phenylglyoxal derivatives, the addition of oligomycin
caused a depolarization of the mitochondrial
membrane potential. This depolarization was completely
blocked by cyclosporin A, a PTP opening inhibitor,
indicating that the depolarization was due to PTP
opening. Collectively, these findings highlight that the
target arginine(s) is functionally linked with the opening/
closing mechanism of the PTP and that the electric
charge and hydrogen bonding of the resulting arginine
adduct influences the conformation of the PTP. These
results are consistent with a model where the target
arginine plays a role as a voltage sensor