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

Hung Li Wang, An Hsun Chou, Tu Hsueh Yeh, Allen Hon Lun Li, Ying Ling Chen, Yu Li Kuo, Shu Ru Tsai, Szu Tzu Yu

Research output: Contribution to journalArticle

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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 (NΔ35), 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 (CΔ145) 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.

Original languageEnglish
Pages (from-to)216-226
Number of pages11
JournalNeurobiology of Disease
Volume28
Issue number2
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

Fingerprint

Cytochromes c
Parkinson Disease
Phosphotransferases
Atractyloside
Caspase 3
Cell Death
Cytochromes c1
Recessive Genes
Mutation
Proteasome Inhibitors

Keywords

  • Cytochrome c
  • PARK6
  • Parkinson's disease
  • PTEN-induced kinase 1

ASJC Scopus subject areas

  • Neurology

Cite this

PINK1 mutants associated with recessive Parkinson's disease are defective in inhibiting mitochondrial release of cytochrome c. / Wang, Hung Li; Chou, An Hsun; Yeh, Tu Hsueh; Li, Allen Hon Lun; Chen, Ying Ling; Kuo, Yu Li; Tsai, Shu Ru; Yu, Szu Tzu.

In: Neurobiology of Disease, Vol. 28, No. 2, 11.2007, p. 216-226.

Research output: Contribution to journalArticle

Wang, Hung Li ; Chou, An Hsun ; Yeh, Tu Hsueh ; Li, Allen Hon Lun ; Chen, Ying Ling ; Kuo, Yu Li ; Tsai, Shu Ru ; Yu, Szu Tzu. / PINK1 mutants associated with recessive Parkinson's disease are defective in inhibiting mitochondrial release of cytochrome c. In: Neurobiology of Disease. 2007 ; Vol. 28, No. 2. pp. 216-226.
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