Regulation of mitochondrial permeability transition pore by PINK1.

Clement A Gautier, Emilie Giaime, Erica Caballero, Lucía Núñez, Zhiyin Song, David Chan, Carlos Villalobos, Jie Shen

Molecular neurodegeneration 2012 May 25

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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. 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. 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.

Citation

Clement A Gautier, Emilie Giaime, Erica Caballero, Lucía Núñez, Zhiyin Song, David Chan, Carlos Villalobos, Jie Shen. Regulation of mitochondrial permeability transition pore by PINK1. Molecular neurodegeneration. 2012 May 25;7:22