Loss of Pink1 modulates synaptic mitochondrial bioenergetics in the rat striatum prior to motor symptoms: concomitant complex I respiratory defects and increased complex II-mediated respiration

Kelly L. Stauch, Lance M. Villeneuve, Phillip R. Purnell, Brendan M. Ottemann, Katy Emanuel, Howard S Fox

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Purpose: Mutations in PTEN-induced putative kinase 1 (Pink1), a mitochondrial serine/threonine kinase, cause a recessive inherited form of Parkinson's disease (PD). Pink1 deletion in rats results in a progressive PD-like phenotype, characterized by significant motor deficits starting at 4 months of age. Despite the evidence of mitochondrial dysfunction, the pathogenic mechanism underlying disease due to Pink1-deficiency remains obscure. Experimental design: Striatal synaptic mitochondria from 3-month-old Pink1-deficient rats were characterized using bioenergetic and mass spectroscopy (MS)-based proteomic analyses. Results: Striatal synaptic mitochondria from Pink1-deficient rats exhibit decreased complex I-driven respiration and increased complex II-mediated respiration compared with wild-type rats. MS-based proteomics revealed 69 of the 811 quantified mitochondrial proteins were differentially expressed between Pink1-deficient rats and controls. Down-regulation of several electron carrier proteins, which shuttle electrons to reduce ubiquinone at complex III, in the Pink1-knockouts suggests disruption of the linkage between fatty acid, amino acid, and choline metabolism and the mitochondrial respiratory system. Conclusions and clinical relevance: These results suggest that complex II activity is increased to compensate for loss of electron transfer mechanisms due to reduced complex I activity and loss of electron carriers within striatal nerve terminals early during disease progression. This may contribute to the pathogenesis of PD.

Original languageEnglish (US)
Pages (from-to)1205-1217
Number of pages13
JournalProteomics - Clinical Applications
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2016

Keywords

  • Pink1
  • bioenergetics
  • mitochondria
  • synapses

ASJC Scopus subject areas

  • Clinical Biochemistry

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