Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the beta-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders.
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PMID:Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders. 1706 62

Increasing evidence points to mitochondrial dysfunction in Parkinson's disease (PD) associated with complex I dysfunction, but the exact pathways which lead to cell death have not been resolved. 2D-gel electrophoresis profiles of isolated mitochondria from neuroblastoma cells treated with subcytotoxic concentrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-characterized complex I inhibitor, were assessed to identify associated targets. Up to 27 differentially expressed proteins were observed, of which 16 were identified using peptide mass fingerprinting. Changes in protein levels were validated by immunoprobing 1D blots, confirming increases in heat shock cognate 71 kDa (Hsc70), 60 kDa heat shock protein (Hsp60), fumarase, glutamate oxaloacetate transaminase 2, ATP synthase subunit d, and voltage-dependent anion-channel 1 (VDAC1). Immunoprobing of 2D blots revealed isoform changes in Hsc70, Hsp60, and VDAC1. Subcytotoxic concentrations of MPTP modulated a host of mitochondrial proteins including chaperones, metabolic enzymes, oxidative phosphorylation-related proteins, an inner mitochondrial protein (mitofilin), and an outer mitochondrial membrane protein (VDAC1). Early changes in chaperones suggest a regulated link between complex 1 inhibition and protein folding. VDAC1, a multifunctional protein, may have a key role in signaling between mitochondria and the rest of the cell prior to cell death. Our work provides new important information of relevance to PD.
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PMID:Alterations in the mitochondrial proteome of neuroblastoma cells in response to complex 1 inhibition. 2132 48