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Neurobiol Dis. 2007 Nov;28(2):216-26. Epub 2007 Jul 17.

PINK1 mutants associated with recessive Parkinson's disease are defective in inhibiting mitochondrial release of cytochrome c.

Author information

1
Department of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROC. hlwns@mail.cgu.edu.tw

Abstract

Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). We investigated molecular mechanisms underlying PINK1 neuroprotective function and PARK6 mutation-induced loss of PINK1 function. Overexpression of wild-type PINK1 blocked mitochondrial release of apoptogenic cytochrome c, caspase-3 activation and apoptotic cell death induced by proteasome inhibitor MG132. N-terminal truncated PINK1 (NDelta35), which lacks mitochondrial localization sequence, did not block MG132-induced cytochrome c release and cytotoxicity. Despite mitochondrial expression, PARK6 mutant (E240K), (H271Q), (G309D), (L347P), (E417G) and C-terminal truncated (CDelta145) PINK1 failed to inhibit MG132-induced cytochrome c release and caspase-3 activation. Overexpression of wild-type PINK1 blocked cytochrome c release and cell death caused by atractyloside, which opens mitochondrial permeability transition pore (mPTP). PARK6 PINK1 mutants failed to inhibit atractyloside-induced cytochrome c release. These results suggest that PINK1 exerts anti-apoptotic effect by inhibiting the opening of mPTP and that PARK6 mutant PINK1 loses its ability to prevent mPTP opening and cytochrome c release.

PMID:
17707122
DOI:
10.1016/j.nbd.2007.07.010
[Indexed for MEDLINE]

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