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

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.

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

“…Furthermore, Pink1 mutant zebrafish show decreases in mitochondrial complex I and III activity [96] . Both parkin and PINK1 mutant patient cells, and cell/animal models have reduced mitochondrial respiration [93,[97][98][99] . Mitochondrial morphological abnormalities have also been reported in both parkin and PINK1 patient cells and models, however both elongation and fragmentation of the mitochondrial network has been observed.…”

Phosphorylation of MCAD selectively rescuesPINK1deficiencies in behavior and metabolism

“…Owing to increasing evidence that PINK1 plays a role in lipid and amino acid metabolic homeostasis ( Senyilmaz et al. , 2015 ; Stauch et al. , 2016 ; Vos et al.…”

Proteomic and functional data sets on synaptic mitochondria from rats with genetic ablation of Parkin

“…Striatal synaptic mitochondrial peptides were analyzed using SWATH data-independent analysis (DIA) mode on a TripleTOF 5600 (SCIEX) followed by targeted data extraction as described previously [10] with PeakView software (v2.1, SCIEX, RRID:SCR_015786 ) using our published reference spectral library [2] , [9] , [11] . CyberT ( http://cybert.ics.uci.edu/ ) [12] was used with a sliding window of 61 and a Bayesian confidence coefficient of 12 and proteins were denoted as significantly altered following multiple-hypothesis testing correction if Benjamini & Hochberg (BH) q -values < 0.05.…”

“…Consistently changed proteins found from the comparison of the striatal synaptic and non-synaptic mitochondria [1] isolated from Parkin KO rats are shown in Table 1 . Furthermore, common differentially expressed proteins in striatal synaptic mitochondria from Parkin KO and PINK1 KO rats [2] are shown in Table 2 .…”

“…Protein expression values listed are log 2 (KO/LEH). List of striatal synaptic mitochondrial proteins significantly altered in PINK1 KO rats obtained from previously published work [2] . UniProt Protein Gene Pink1 KO/LEH Parkin KO/LEH P03889 NADH-ubiquinone oxidoreductase chain 1 Mtnd1 −1.118 −2.151 P11884 Aldehyde dehydrogenase Aldh2 −0.825 −1.279 P12007 Isovaleryl-CoA dehydrogenase Ivd −0.848 −2.947 P15650 Long-chain specific acyl-CoA dehydrogenase Acadl −1.004 −1.179 P20070 NADH-cytochrome b5 reductase 3 Cyb5r3 −1.270 −1.879 P22062 Protein-L-isoaspartate(D-aspartate) O-methyltransferase Pcmt1 −1.009 −1.612 P38718 Mitochondrial pyruvate carrier 2 Mpc2 −1.188 −1.702 P51650 Succinate-semialdehyde dehydrogenase Aldh5a1 −0.854 −2.582 P52504 NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 Ndufs6 1.176 −5.979 P63031 Mitochondrial pyruvate carrier 1 Mpc1 0.905 −2.777 Q64536 [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2 Pdk2 −0.955 −1.557 Q68FU3 Electron transfer flavoprotein subunit beta Etfb −1.424 −2.352 Q6B345 Protein S100-A11 S100a11 1.256 −2.990 Q75Q41 Mitochondrial import receptor subunit TOM22 homolog Tomm22 −1.435 −2.144 …”