TY - JOUR
T1 - Loss of Pink1 modulates synaptic mitochondrial bioenergetics in the rat striatum prior to motor symptoms
T2 - concomitant complex I respiratory defects and increased complex II-mediated respiration
AU - Stauch, Kelly L.
AU - Villeneuve, Lance M.
AU - Purnell, Phillip R.
AU - Ottemann, Brendan M.
AU - Emanuel, Katy
AU - Fox, Howard S
N1 - Funding Information:
This study was supported by a Michael J. Fox Foundation (MJFF) grant #9524. We are grateful for technical support received from the UNMC Mass Spectrometry and Proteomics Core Facility, especially Dr. Pawel Ciborowski and Melinda Wojtkiewicz.
Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Pink1
KW - bioenergetics
KW - mitochondria
KW - synapses
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U2 - 10.1002/prca.201600005
DO - 10.1002/prca.201600005
M3 - Article
C2 - 27568932
AN - SCOPUS:84988350538
SN - 1862-8346
VL - 10
SP - 1205
EP - 1217
JO - Proteomics - Clinical Applications
JF - Proteomics - Clinical Applications
IS - 12
ER -