Effects of 1-methyl-4-phenylpyridinium on isolated rat brain mitochondria: evidence for a primary involvement of energy depletion

Bates, T. E. and Heales, S. J. and Davies, S. E. and Boakye, P. and Clark, J. B. (1994) Effects of 1-methyl-4-phenylpyridinium on isolated rat brain mitochondria: evidence for a primary involvement of energy depletion. Journal of neurochemistry, 63 (2). pp. 640-648. ISSN 0022-3042

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Official URL: http://dx.doi.org/10.1046/j.1471-4159.1994.6302064...

Abstract

The effects of 1-methyl-4-phenylpyridinium (MPP+) on the oxygen consumption, ATP production, H2O2 production, and mitochondrial NADH-CoQ1 reductase (complex I) activity of isolated rat brain mitochondria were investigated. Using glutamate and malate as substrates, concentrations of 10-100 microM MPP+ had no effect on state 4 (-ADP) respiration but decreased state 3 (+ADP) respiration and ATP production. Incubating mitochondria with ADP for 30 min after loading with varying concentrations of MPP+ produced a concentration-dependent decrease in H2O2 production. Incubation of mitochondria with ADP for 60 min after loading with 100 microM MPP+ caused no loss of complex I activity after washing of MPP+ from the mitochondrial membranes. These data are consistent with MPP+ initially binding specifically to complex I and inhibiting both the flow of reducing equivalents and the production of H2O2 by the mitochondrial respiratory chain, without irreversibly damaging complex I. However, mitochondria incubated with H2O2 in the presence of Cu2+ ions showed decreased complex I activity. This study provides additional evidence that cellular damage initiated by MPP+ is due primarily to energy depletion caused by specific binding to complex I, any increased damage due to free radical production by mitochondria being a secondary effect.

Item Type:Article
Additional Information:The effects of 1-methyl-4-phenylpyridinium (MPP+) on the oxygen consumption, ATP production, H2O2 production, and mitochondrial NADH-CoQ1 reductase (complex I) activity of isolated rat brain mitochondria were investigated. Using glutamate and malate as substrates, concentrations of 10-100 microM MPP+ had no effect on state 4 (-ADP) respiration but decreased state 3 (+ADP) respiration and ATP production. Incubating mitochondria with ADP for 30 min after loading with varying concentrations of MPP+ produced a concentration-dependent decrease in H2O2 production. Incubation of mitochondria with ADP for 60 min after loading with 100 microM MPP+ caused no loss of complex I activity after washing of MPP+ from the mitochondrial membranes. These data are consistent with MPP+ initially binding specifically to complex I and inhibiting both the flow of reducing equivalents and the production of H2O2 by the mitochondrial respiratory chain, without irreversibly damaging complex I. However, mitochondria incubated with H2O2 in the presence of Cu2+ ions showed decreased complex I activity. This study provides additional evidence that cellular damage initiated by MPP+ is due primarily to energy depletion caused by specific binding to complex I, any increased damage due to free radical production by mitochondria being a secondary effect.
Keywords:MPTP, MPP+, 1-methyl-4-phenylpyridinium, Brain, Mitochondria, Hydrogen peroxide, H202, ATP, oxidative stress, Complex I
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
B Subjects allied to Medicine > B140 Neuroscience
B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
A Medicine and Dentistry > A300 Clinical Medicine
Divisions:College of Science > School of Life Sciences
ID Code:5363
Deposited By: Timothy Bates
Deposited On:18 May 2012 08:49
Last Modified:18 May 2012 08:49

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