Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1

Mei Cui, Xiangna Tang, Whitney V. Christian, Yisang Yoon, Kim Tieu

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Mutations in the mitochondrial encoded protein PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson disease (PD). In mammalian cells, mutant PINK1 has been reported to promote fission or inhibit fusion in mitochondria; however, the mechanism by which this process occurs remains elusive. Using an ecdysone-inducible expression system in mammalian dopaminergic neuronal cells, we report here that human mutant PINK1 (L347P and W437X) mediates an overall fission effect by increasing the ratio of mitochondrial fission over fusion proteins, leading to excessive dysfunctional fragmented mitochondria. Knocking down endogenous Pink1 produces similar effects. In contrast, overexpressing human wild type PINK1 produces a pro-fusion effect by increasing the ratio of mitochondrial fusion/fission proteins without resulting in functionally compromised mitochondria. Parkin knockdown blocks the imbalance in fission/fusion proteins. Furthermore, overexpressing parkin and ubiquitin increases degradation of the mitochondrial fission hFis1 protein, suggesting PINK1 and parkin maintain proper mitochondrial function and integrity via the fission/fusion machinery. Through genetic manipulations and treatment with the small molecule mitochondrial division inhibitor (mdivi-1), which inhibits DLP1/Drp1, both structural and functional mitochondrial defects induced by mutant PINK1 were attenuated, highlighting a potential novel therapeutic avenue for Parkinson disease.

Original languageEnglish (US)
Pages (from-to)11740-11752
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number15
DOIs
StatePublished - Apr 9 2010

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Mitochondrial Dynamics
Fusion reactions
Mitochondria
Parkinson Disease
Proteins
Ecdysone
Mitochondrial Proteins
Ubiquitin
Machinery
PTEN-induced putative kinase
Cells
Degradation
Defects
Mutation
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. / Cui, Mei; Tang, Xiangna; Christian, Whitney V.; Yoon, Yisang; Tieu, Kim.

In: Journal of Biological Chemistry, Vol. 285, No. 15, 09.04.2010, p. 11740-11752.

Research output: Contribution to journalArticle

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