35 Protective action of synthetic diarylamines on mitochondrial permeability transition pore

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Mitochondria can undergo a generalised increase of the permeability of the inner membrane, called mitochondrial permeability transition (MPT), due to the formation of non-specific pores (MPTP), which is an early key event in apoptosis, causing activation of the caspases through release of cytochrome c.1 Calcium overload and oxidative stress combine with other factors to induce the MPT. Inhibition of the MPTP is accepted as a therapeutic approach in pathological situations, namely by attenuation of the reactive species accumulation through antioxidants usage. In particular, MPTP is considered a therapeutic target for cardioprotection, especially in ischaemia/reperfusion primarily to its central role in cell death.2 Considering this we studied the influence of two new synthetic di(hetero)arylamines, MJQ1 and MJQ5, both sharing radical scavenger capabilities in the nM range,3 on the protection of MPTP, attempting to provide relevant hints about their action mechanisms. We detect that MJQ1 rising the pore after open induction with different oxidant pairs (H2O2/Fe2+; t- BHP, Ca2+/Pi). In mitochondrial measurements of calcium fluxes the presence of MJQ1 allowed mitochondria full accumulation of calcium, while MJQ5 also reveal its protective action by causing a delay in the loss of mitochondrial accumulated calcium. Relatively to mitochondrial osmotic volume changes both diarylamines decreased mitochondrial swelling. MJQ1 inhibited the swelling of de-energised mitochondria loaded with calcium indicating a direct effect on MPTP component(s). As opposed to MJQ1, MJQ5 revealed a protective action in the high conductance state of MPTP due to its antioxidant properties.

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