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The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics.

Dinkova-Kostova AT, Baird L, Holmström KM, Meyer CJ, Abramov AY - Biochem. Soc. Trans. (2015)

Bottom Line: One way by which Nrf2 influences mitochondrial activity is through increasing the availability of substrates (NADH and FADH2) for respiration.Another way is through accelerating fatty acid oxidation (FAO).These findings reinforce the reciprocal relationship between oxidative phosphorylation and the cellular redox state, and highlight the key role of Nrf2 in regulating this balance.

View Article: PubMed Central - PubMed

Affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY Scotland, U.K. Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. a.dinkovakostova@dundee.ac.uk a.abramov@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Inducers of the Keap1-Nrf2 pathway restore the mitochondrial membrane potential in PINK1-deficient primary neurons and astrocytes and protects against dopamine-induced cell death(A) Primary midbrain neurons and astrocytes isolated from WT and PINK1-KO mice were treated with sulforaphane (50 nM, 24 h) or RTA-408 (20 nM, 24 h) and loaded with 25 nM tetramethylrhodamine methyl ester (TMRM) for 40 min for determination of the mitochondrial membrane potential. (B) Effect of pre-treatment with inducers for 24 h before and during the time (a further 24 h) of exposure of co-cultures of neurons and astrocytes to 50 μM dopamine. Cell death was measured by counting the dead cells (Propidium Iodide, red fluorescence) and live cells (Hoechst 33342, blue fluorescence). Blank indicates cells treated with solvent (0.1% DMSO). *P<0.01; **P<0.001.
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Figure 3: Inducers of the Keap1-Nrf2 pathway restore the mitochondrial membrane potential in PINK1-deficient primary neurons and astrocytes and protects against dopamine-induced cell death(A) Primary midbrain neurons and astrocytes isolated from WT and PINK1-KO mice were treated with sulforaphane (50 nM, 24 h) or RTA-408 (20 nM, 24 h) and loaded with 25 nM tetramethylrhodamine methyl ester (TMRM) for 40 min for determination of the mitochondrial membrane potential. (B) Effect of pre-treatment with inducers for 24 h before and during the time (a further 24 h) of exposure of co-cultures of neurons and astrocytes to 50 μM dopamine. Cell death was measured by counting the dead cells (Propidium Iodide, red fluorescence) and live cells (Hoechst 33342, blue fluorescence). Blank indicates cells treated with solvent (0.1% DMSO). *P<0.01; **P<0.001.

Mentions: Oxidative stress and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease. Mutations in the mitochondrial serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) are associated with hereditary early-onset Parkinson's disease [48]. Recently, we found that PINK1 deficiency is associated with inhibition of mitochondrial respiration due to lack of mitochondrial substrates that lead to decrease in ∆Ψm (Figure 3A) [49,50]. Provision of PINK1-deficient cells with mitochondrial substrates restores ∆Ψm and makes these cells less vulnerable to dopamine-induced neurodegeneration [51].


The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics.

Dinkova-Kostova AT, Baird L, Holmström KM, Meyer CJ, Abramov AY - Biochem. Soc. Trans. (2015)

Inducers of the Keap1-Nrf2 pathway restore the mitochondrial membrane potential in PINK1-deficient primary neurons and astrocytes and protects against dopamine-induced cell death(A) Primary midbrain neurons and astrocytes isolated from WT and PINK1-KO mice were treated with sulforaphane (50 nM, 24 h) or RTA-408 (20 nM, 24 h) and loaded with 25 nM tetramethylrhodamine methyl ester (TMRM) for 40 min for determination of the mitochondrial membrane potential. (B) Effect of pre-treatment with inducers for 24 h before and during the time (a further 24 h) of exposure of co-cultures of neurons and astrocytes to 50 μM dopamine. Cell death was measured by counting the dead cells (Propidium Iodide, red fluorescence) and live cells (Hoechst 33342, blue fluorescence). Blank indicates cells treated with solvent (0.1% DMSO). *P<0.01; **P<0.001.
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Related In: Results  -  Collection

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Figure 3: Inducers of the Keap1-Nrf2 pathway restore the mitochondrial membrane potential in PINK1-deficient primary neurons and astrocytes and protects against dopamine-induced cell death(A) Primary midbrain neurons and astrocytes isolated from WT and PINK1-KO mice were treated with sulforaphane (50 nM, 24 h) or RTA-408 (20 nM, 24 h) and loaded with 25 nM tetramethylrhodamine methyl ester (TMRM) for 40 min for determination of the mitochondrial membrane potential. (B) Effect of pre-treatment with inducers for 24 h before and during the time (a further 24 h) of exposure of co-cultures of neurons and astrocytes to 50 μM dopamine. Cell death was measured by counting the dead cells (Propidium Iodide, red fluorescence) and live cells (Hoechst 33342, blue fluorescence). Blank indicates cells treated with solvent (0.1% DMSO). *P<0.01; **P<0.001.
Mentions: Oxidative stress and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease. Mutations in the mitochondrial serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) are associated with hereditary early-onset Parkinson's disease [48]. Recently, we found that PINK1 deficiency is associated with inhibition of mitochondrial respiration due to lack of mitochondrial substrates that lead to decrease in ∆Ψm (Figure 3A) [49,50]. Provision of PINK1-deficient cells with mitochondrial substrates restores ∆Ψm and makes these cells less vulnerable to dopamine-induced neurodegeneration [51].

Bottom Line: One way by which Nrf2 influences mitochondrial activity is through increasing the availability of substrates (NADH and FADH2) for respiration.Another way is through accelerating fatty acid oxidation (FAO).These findings reinforce the reciprocal relationship between oxidative phosphorylation and the cellular redox state, and highlight the key role of Nrf2 in regulating this balance.

View Article: PubMed Central - PubMed

Affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY Scotland, U.K. Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. a.dinkovakostova@dundee.ac.uk a.abramov@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus