Abstract
Mastoparan facilitates opening of the mitochondrial permeability transition pore through an apparent bimodal mechanism of action. In the submicromolar concentration range, the action of mastoparan is dependent upon the medium Ca2+ and phosphate concentration and is subject to inhibition by cyclosporin A. At concentrations above 1 microM, pore induction by mastoparan occurs without an apparent Ca2+ requirement and in a cyclosporin A insensitive manner. Studies utilizing phospholipid vesicles show that mastoparan perturbs bilayer membranes across both concentration ranges, through a mechanism which is strongly dependent upon transmembrane potential. However, solute size exclusion studies suggest that the pores formed in mitochondria in response to both low and high concentrations of mastoparan are the permeability transition pore. It is proposed that low concentrations of mastoparan influence the pore per se, with higher concentrations having the additional effect of depolarizing the mitochondrial inner membrane through an action exerted upon the lipid phase. It may be the combination of these effects which allow pore opening in the absence of Ca2+ and in the presence of cyclosporin A, although other interpretations remain viable. A comparison of the activities of mastoparan and its analog, MP14, on mitochondria and phospholipid vesicles provides an initial indication that a G-protein may participate in regulation of the permeability transition pore. These studies draw attention to peptides, in a broad sense, as potential pore regulators in cells, under both physiological and pathological conditions.
Highlights
From the Department of Medical Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210 and the Hormel Institute, University of Minnesota, Austin, Minnesota 55912
CSA-sensitive and Insensitive Actions of Mastoparan on the Permeability Transition-Fig. 1 demonstrates that 1.0 J.LM mastoparan can be used in place of exogenous Ca2 + to induce a permeability transition in mitochondria incubated in the presence of succinate and 5 mM Pi' Under these conditions, the depolarization and swelling provoked by mastoparan arise from opening the permeability transition pore (PTP) as indicated by the inhibitory action of CSA (Fig. 1)
When Pi is present at a concentration of 5 mM, 1.0 p..M mastoparan markedly stimulates the transition across a range ofCa2 + loads (Fig. 3A), little or no activity is seen in the absence of exogenous Pi (Fig. 3B)
Summary
From the Department of Medical Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210 and the Hormel Institute, University of Minnesota, Austin, Minnesota 55912. It is proposed that low concentrations of mastoparan influence the pore per se, with higher concentrations having the additional effect of depolarizing the mitochondrial inner membrane through an action exerted upon the lipid phase It may be the combination of these effects which allow pore opening in the absence of Ca2 + and in the presence of cyclosporin A, other interpretations remain viable. A comparison of the activities of mastoparan and its analog, MP14, on mitochondria and phospholipid vesicles provides an initial indication that a G-protein may participate in regulation of the permeability transition pore These studies draw attention to peptides, in a broad sense, as potential pore regulators in cells, under both physiological and pathological conditions. Ation of the transition with cell injury mechanisms and the identification of ~yclosporin A (CSA)! as a potent inhibitor of the phenomenon [11,12,13,14] has created a high level of interest in this aspect of mitochondrial research
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
