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Abstract
The peripheral-type benzodiazepine receptors (PBR) are localized on the outer mitochondrial membrane, as a constituent of mitochondrial permeability transition (MPT)-pore. Among its hypothesized functions, the regulation of the mitochondrial respiratory chain and apoptosis have been suggested; in addition alterations of PBR site density have been shown in some neuropathologic conditions with putative mitochondrial involvement. The aim of this work has been to evaluate PBR kinetic binding parameters in platelets from patients affected by mitochondrial disorders (MD) with large-scale mitochondrial DNA deletions and reduced cytochrome c oxidase activity. Using the specific PBR radioligand [(3) H] PK 11195, the kinetic binding parameters of PBR sites were determined in platelet membrane of 15 healthy subjects and 11 patients affected by different form of MD. Significant changes of dissociation constant (K(d)) and maximal number of binding sites (B(max)) values were evidenced in platelets of patients versus controls. In all patients the B(max) values were decreased (2,387.0 +/- 305.6 fmol/ mg proteins versus 4889.0 +/- 357.8 fmol/mg proteins, p< 0.05), whereas the K(d) values were higher in patients than controls (13.18 +/- 2.06 nM versus 5.63 +/- 0.46 nM, p< 0.05). These data suggest that the kinetic binding parameters of PBR are altered in MD and that the observed changes might be related to the mitochondrial dysfunction associated with MD.
Highlights
The mitochondrial disorders (MD) are genetically and phenotypically heterogeneous groups of disorders caused by structural and functional abnormalities in mitochondria
These data suggest that the kinetic binding parameters of peripheral-type benzodiazepine receptors (PBR) are altered in MD and that the observed changes might be related to the mitochondrial dysfunction associated with MD
Eight patients were affected by chronic external progressive ophthalmoplegia (CPEO), sporadic in six and inherited autosomal dominant in two cases, two by myopathy with exercise intolerance, and one by autosomically dominant inherited encephalomyopathy, bipolar disorder, and multiple symmetrical lipomatosis
Summary
The mitochondrial disorders (MD) are genetically and phenotypically heterogeneous groups of disorders caused by structural and functional abnormalities in mitochondria. Impaired ETC functioning leads to a number of deleterious consequences including decreased ATP production, impaired calcium buffering, and generation of free radicals. These changes lead to further mitochondrial damage such as oxidation of mitochondrial DNA (mtDNA), proteins, and lipids. The peripheral-type benzodiazepine receptors (PBR) are localized on the outer mitochondrial membrane, as a constituent of mitochondrial permeability transition (MPT)-pore. The aim of this work has been to evaluate PBR kinetic binding parameters in platelets from patients affected by mitochondrial disorders (MD) with large-scale mitochondrial DNA deletions and reduced cytochrome c oxidase activity. Materials and Methods: Using the specific PBR radioligand [3H] PK 11195, the kinetic binding parameters of PBR sites were determined in platelet membrane of 15 healthy subjects and 11 patients affected by different form of MD
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