RT info:eu-repo/semantics/article
T1 Regulation of mitochondrial permeability transition pore by PINK1
A1 Gautier, Clement A.
A1 Giaime, Emilie
A1 Caballero, Erica
A1 Núñez Llorente, Lucía
A1 Song, Zhiyin
A1 Chan, David
A1 Villalobos Jorge, Carlos
A1 Shen, Jie
K1 Parkinson’s disease
K1 Enfermedad de Parkinson
K1 Mitochondrial respiration
K1 Respiración celular
K1 Mitochondrial proteins
K1 Proteínas mitocondriales
K1 Calcium
K1 Calcio
AB 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.
PB BioMed Central
SN 1750-1326
YR 2012
FD 2012
LK http://uvadoc.uva.es/handle/10324/45057
UL http://uvadoc.uva.es/handle/10324/45057
LA eng
NO Molecular Neurodegeneration, 2012, vol. 7. 15 p.
NO Producción Científica
DS UVaDOC
RD 21-dic-2024