Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects

Taku Amo, Shigeto Sato, Shinji Saiki, Alexander M. Wolf, Masaaki Toyomizu, Clement A. Gautier, Jie Shen, Shigeo Ohta, Nobutaka Hattori

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Mutations in PTEN-induced putative kinase 1 (PINK1) cause a recessive form of Parkinson's disease (PD). PINK1 is associated with mitochondrial quality control and its partial knock-down induces mitochondrial dysfunction including decreased membrane potential and increased vulnerability against mitochondrial toxins, but the exact function of PINK1 in mitochondria has not been investigated using cells with null expression of PINK1. Here, we show that loss of PINK1 caused mitochondrial dysfunction. In PINK1-deficient (PINK1-/-) mouse embryonic fibroblasts (MEFs), mitochondrial membrane potential and cellular ATP levels were decreased compared with those in littermate wild-type MEFs. However, mitochondrial proton leak, which reduces membrane potential in the absence of ATP synthesis, was not altered by loss of PINK1. Instead, activity of the respiratory chain, which produces the membrane potential by oxidizing substrates using oxygen, declined. H2O2 production rate by PINK1-/- mitochondria was lower than PINK1+/+ mitochondria as a consequence of decreased oxygen consumption rate, while the proportion (H2O2 production rate per oxygen consumption rate) was higher. These results suggest that mitochondrial dysfunctions in PD pathogenesis are caused not by proton leak, but by respiratory chain defects.

Original languageEnglish
Pages (from-to)111-118
Number of pages8
JournalNeurobiology of Disease
Volume41
Issue number1
DOIs
Publication statusPublished - 2011 Jan

Keywords

  • Membrane potential
  • Mitochondria
  • Modular kinetic analysis
  • Oxidative phosphorylation
  • PINK1
  • Parkin
  • Parkinson's disease
  • Proton leak
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neurology

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