Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.
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PMID:Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. 1714 10

Mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. To investigate the mechanism of PINK1 pathogenesis, we used the Drosophila Pink1 knockout (KO) model. In mitochondria isolated from Pink1-KO flies, mitochondrial respiration driven by the electron transport chain (ETC) is significantly reduced. This reduction is the result of a decrease in ETC complex I and IV enzymatic activity. As a consequence, Pink1-KO flies also display a reduced mitochondrial ATP synthesis. Because mitochondrial dynamics is important for mitochondrial function and Pink1-KO flies have defects in mitochondrial fission, we explored whether fission machinery deficits underlie the bioenergetic defect in Pink1-KO flies. We found that the bioenergetic defects in the Pink1-KO can be ameliorated by expression of Drp1, a key molecule in mitochondrial fission. Further investigation of the ETC complex integrity in wild type, Pink1-KO, PInk1-KO/Drp1 transgenic, or Drp1 transgenic flies indicates that the reduced ETC complex activity is likely derived from a defect in the ETC complex assembly, which can be partially rescued by increasing mitochondrial fission. Taken together, these results suggest a unique pathogenic mechanism of PINK1 PD: The loss of PINK1 impairs mitochondrial fission, which causes defective assembly of the ETC complexes, leading to abnormal bioenergetics.
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PMID:Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission. 2176 65

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective dopaminergic cell loss in the substantia nigra, but its pathogenesis remains unclear. The recessively inherited familial PD genes PARK2 and PARK6 have been attributed to mutations in the Parkin and PTEN-induced kinase 1 (PINK1) genes, respectively. Recent reports suggest that PINK1 works upstream of Parkin in the same pathway to regulate mitochondrial dynamics and/or conduct autophagic clearance of damaged mitochondria. This phenomenon is preserved from Drosophila to human cell lines but has not been demonstrated in a vertebrate animal model in vivo. Here, we developed a medaka fish (Oryzias latipes) model that is deficient in Pink1 and Parkin. We found that despite the lack of a conspicuous phenotype in single mutants for Pink1 or Parkin, medaka that are deficient in both genes developed phenotypes similar to that of human PD: late-onset locomotor dysfunction, a decrease in dopamine levels and a selective degeneration of dopaminergic neurons. Further analysis also revealed defects in mitochondrial enzymatic activity as well as cell death. Consistently, PINK1 and Parkin double-deficient MEF showed a further decrease in mitochondrial membrane potential and mitochondrial complex I activity as well as apoptosis compared with single-deficient MEF. Interestingly, these mitochondrial abnormalities in Parkin-deficient MEF were compensated by exogenous PINK1, but not by disease-related mutants. These results suggest that PINK1 and Parkin work in a complementary way to protect dopaminergic neurons by maintaining mitochondrial function in vertebrates.
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PMID:PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates. 2344 26

PTEN-induced kinase 1 (PINK1) mutations are responsible for an autosomal recessive, familial form of Parkinson's disease. PINK1 protein is a Ser/Thr kinase localized to the mitochondrial membrane and is involved in many processes including mitochondrial trafficking, mitophagy, and proteasomal function. Using a new PINK1 knockout (PINK1 KO) rat model, we found altered brain metabolomic markers using magnetic resonance spectroscopy, identified changes in mitochondrial pathways with quantitative proteomics using sequential window acquisition of all theoretical spectra (SWATH) mass spectrometry, and demonstrated mitochondrial functional alterations through measurement of oxygen consumption and acidification rates. The observed alterations included reduced creatine, decreased levels of complex I of the electron transport chain, and increased proton leak in the electron transport chain in PINK1 KO rat brains. In conjunction, these results demonstrate metabolomic and mitochondrial alterations occur during the asymptomatic phase of Parkinson's disease in this model. These results indicate both potential early diagnostic markers and therapeutic pathways that can be used in PD.
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PMID:Early Expression of Parkinson's Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats. 2542 Dec 6

T-2 toxin is the most toxic member of trichothecene mycotoxin. So far, the mechanism of mitochondrial toxicity and protective mechanism in mammalian cells against T-2 toxin are not fully understood. In this study, we aimed to investigate the cellular and mitochondrial toxicity of T-2 toxin, and the cellular protective mechanisms in rat pituitary GH3 cells. We showed that T-2 toxin significantly increased reactive oxygen species (ROS) and DNA damage and caused apoptosis in GH3 cells. T-2 toxin induced abnormal cell morphology, cytoplasm and nuclear shrinkage, nuclear fragmentation and formation of apoptotic bodies and autophagosomes. The mitochondrial degradative morphologies included local or total cristae collapse and small condensed mitochondria. T-2 toxin decreased the mitochondrial membrane potential. However, T-2 toxin significantly increased the superoxide dismutase (SOD) activity and expression of antioxidant genes glutathione peroxidase 1 (GPx-1), catalase (CAT), mitochondria-specific SOD-2 and mitochondrial uncoupling protein-1, -2 and -3 (UCP-1, 2 and 3). Interestingly, T-2 toxin increased adenosine triphosphate (ATP) levels and mitochondrial complex I activity, and increased the expression of most of mitochondrial electron transport chain subunits tested and critical transcription factors controlling mitochondrial biogenesis and mitochondrial DNA transcription and replication. T-2 toxin increased mitophagic activity by increasing the expression of mitophagy-specific proteins NIP-like protein X (NIX), PTEN-induced putative kinase protein 1 (PINK1) and E3 ubiquitin ligase Parkin. T-2 toxin activated the protective protein kinase A (PKA) signaling pathway, which activated the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/PINK1/Parkin pathway to mediate mitophagy. Taken together, our results suggested that the mammalian cells could increase their resistance against T-2 toxin by increasing the antioxidant activity, mitophagy and mitochondrial function.
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PMID:Protective mechanisms involving enhanced mitochondrial functions and mitophagy against T-2 toxin-induced toxicities in GH3 cells. 2987 Jul 51