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See detailDopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.
Burbulla, Lena F.; Song, Pingping; Mazzulli, Joseph R. et al

in Science (New York, N.Y.) (2017), 357(6357), 1255-1261

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains ... [more ▼]

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis. [less ▲]

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See detailPINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.
Morais, Vanessa A.; Haddad, Dominik; Craessaerts, Katleen et al

in Science (New York, N.Y.) (2014), 344(6180), 203-7

Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial ... [more ▼]

Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations. [less ▲]

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See detailThree-dimensional structural view of the central metabolic network of Thermotoga maritima.
Zhang, Ying; Thiele, Ines UL; Weekes, Dana et al

in Science (New York, N.Y.) (2009), 325(5947), 1544-1549

Metabolic pathways have traditionally been described in terms of biochemical reactions and metabolites. With the use of structural genomics and systems biology, we generated a three-dimensional ... [more ▼]

Metabolic pathways have traditionally been described in terms of biochemical reactions and metabolites. With the use of structural genomics and systems biology, we generated a three-dimensional reconstruction of the central metabolic network of the bacterium Thermotoga maritima. The network encompassed 478 proteins, of which 120 were determined by experiment and 358 were modeled. Structural analysis revealed that proteins forming the network are dominated by a small number (only 182) of basic shapes (folds) performing diverse but mostly related functions. Most of these folds are already present in the essential core (approximately 30%) of the network, and its expansion by nonessential proteins is achieved with relatively few additional folds. Thus, integration of structural data with networks analysis generates insight into the function, mechanism, and evolution of biological networks. [less ▲]

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