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Título
Regulation of mitochondrial permeability transition pore by PINK1
Autor
Año del Documento
2012
Editorial
BioMed Central
Descripción
Producción Científica
Documento Fuente
Molecular Neurodegeneration, 2012, vol. 7. 15 p.
Abstract
Background: Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) have been linked to familial Parkinson’s disease, but the underlying pathogenic mechanism remains unclear. We previously reported that loss of PINK1 impairs mitochondrial respiratory activity in mouse brains. Results: In this study, we investigate how loss of PINK1 impairs mitochondrial respiration using cultured primary fibroblasts and neurons. We found that intact mitochondria in PINK1−/− cells recapitulate the respiratory defect in isolated mitochondria from PINK1−/− mouse brains, suggesting that these PINK1−/− cells are a valid experimental system to study the underlying mechanisms. Enzymatic activities of the electron transport system complexes are normal in PINK1−/− cells, but mitochondrial transmembrane potential is reduced. Interestingly, the opening of the mitochondrial permeability transition pore (mPTP) is increased in PINK1−/− cells, and this genotypic difference between PINK1−/− and control cells is eliminated by agonists or inhibitors of the mPTP. Furthermore, inhibition of mPTP opening rescues the defects in transmembrane potential and respiration in PINK1−/− cells. Consistent with our earlier findings in mouse brains, mitochondrial morphology is similar between PINK1−/− and wild-type cells, indicating that the observed mitochondrial functional defects are not due to morphological changes. Following FCCP treatment, calcium increases in the cytosol are higher in PINK1−/− compared to wild-type cells, suggesting that intra-mitochondrial calcium concentration is higher in the absence of PINK1. Conclusions: Our findings show that loss of PINK1 causes selective increases in mPTP opening and mitochondrial calcium, and that the excessive mPTP opening may underlie the mitochondrial functional defects observed in PINK1−/− cells.
Palabras Clave
Parkinson’s disease
Enfermedad de Parkinson
Mitochondrial respiration
Respiración celular
Mitochondrial proteins
Proteínas mitocondriales
Calcium
Calcio
ISSN
1750-1326
Revisión por pares
SI
Patrocinador
National Institute of Neurological Disorders and Stroke (grant R01 NS041779)
Version del Editor
Propietario de los Derechos
© 2012 BioMed Central
Idioma
eng
Tipo de versión
info:eu-repo/semantics/publishedVersion
Derechos
openAccess
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