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 induced by acute complex I inhibition with 1-methyl-4-phenylpyridinium ion activated biphasically the stress-activated c-Jun N-terminal kinase (JNK) and the early transcription factor nuclear factor-kappaB (NF-kappaB) in SH-SY5Y neuroblastoma cells. Early JNK activation was dependent on mitochondrial adenine nucleotide translocator (ANT) activity, whereas late-phase JNK activation and the cleavage of signaling proteins Raf-1 and mitogen-activated protein kinase (MAPK) kinase (MEK) kinase (MEKK)-1 appeared to be ANT-independent. Early NF-kappaB activation depended on MEK, later activation required an intact electron transport chain (ETC), and Parkinson's disease (PD) cybrid (mitochondrial transgenic cytoplasmic hybrid) cells had increased basal NF-kappaB activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF-kappaB responses, which are increased by PD mitochondrial genes amplified in cybrid cells. Irreversible commitment to apoptosis in this cell model may derive from loss of Raf-1 and cleavage/activation of MEKK-1, processes reported in other models to be caspase-mediated. Therapeutic strategies that reduce mitochondrial activation of proapoptotic MAPK modules, i.e., JNK, and enhance survival pathways, i.e., NF-kappaB, may offer neuroprotection in this debilitating disease.
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PMID:Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of Parkinson's disease. 1073 93

Mitochondria, besides playing a central role in energy metabolism within the cell, are involved in a cohort of other processes like cellular differentiation and apoptosis. Investigations during recent few years have shown that protein kinases, including PKA, PKB/Akt, PKC, Raf-1, p38 MAPK, JNK, ERK1/2, Src, Fyn and Csk, may directly interact with mitochondrial proteins. Their role mainly concentrates at phosphorylation of pro- and anti-apoptotic proteins (Bad, Bax, Bcl-2, Bcl-xL), phosphorylation/modification of electron transport chain proteins (complex I, COIV), MPTP forming proteins VDAC and ANT, proteins of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) and phospholipid scramblase 3 (PLSCR3). Many experimental data showed the presence of protein kinases in the outer and inner mitochondrial membranes as well as in the mitochondrial matrix during in vitro cell stimulations, in neurodegenerative diseases and in in vivo ischaemia heart preconditioning. These data show that translocation of protein kinases to mitochondria plays an important role especially during ischaemia/reperfusion in brain and heart.
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PMID:[Protein kinases in mitochondria]. 1880 32

Rotenone (ROT) is a widely used inhibitor of complex I (CI), the first complex of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, particularly at high concentrations ROT was also described to display off-target effects. Here we studied how ROT affected in vitro primary murine myotube formation. We demonstrate that myotube formation is specifically inhibited by ROT (10-100nM), but not by piericidin A (PA; 100nM), another CI inhibitor. At 100nM, both ROT and PA fully blocked myoblast oxygen consumption. Knock-down of Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) and, to a lesser extent ROCK1, prevented the ROT-induced inhibition of myotube formation. Moreover, the latter was reversed by inhibiting Raf-1 activity. In contrast, ROT-induced inhibition of myotube formation was not prevented by knock-down of RhoA. Taken together, our results support a model in which ROT reduces primary myotube formation independent of its inhibitory effect on CI-driven mitochondrial ATP production, but via a mechanism primarily involving the Raf-1/ROCK2 pathway.
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PMID:Rotenone inhibits primary murine myotube formation via Raf-1 and ROCK2. 2582 55