Effects of 1‐Methyl‐4‐Phenylpyridinium on Isolated Rat Brain Mitochondria: Evidence for a Primary Involvement of Energy Depletion

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 µM 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 µM 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.

Mitochondria Targeted Peptides Protect Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Neurotoxicity

“…This concentration, however, significantly reduced mitochondrial oxygen consumption and ATP production. A rapid loss of intracellular ATP has also been reported by other investigators (2,7,15) and may be the major cause of cell death. Glucose supplementation to enhance anaerobic glycolysis was able to protect against MPP þ toxicity in C6 glioma cells (39), and infusion of the ketone body D-b-hydroxybutyrate also produced protection against MPTP neurotoxicity in mice (33).…”

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP+)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP+in PC12 Cells

“…The neurotoxic effects in vivo of MPTP are dependent on the conversion to its active metabolite 1-methyl-4-phenylpyridinium (MPP ϩ ) by monoamine oxidase B in glial cells and the uptake into neurons through transporters (Tipton and Singer, 1993;Kitayama et al, 1998). MPP ϩ induces an inhibition of complex I activity of the mitochondrial respiratory chain and cellular ATP depletion and a loss of mitochondrial transmembrane potential, resulting in cell death (Bates et al, 1994).…”

“…The neurotoxic effects in vivo of MPTP are dependent on the conversion to its active metabolite 1-methyl-4-phenylpyridinium (MPP ϩ ) by monoamine oxidase B in glial cells and the uptake into neurons through transporters (Tipton and Singer, 1993;Kitayama et al, 1998). MPP ϩ induces an inhibition of complex I activity of the mitochondrial respiratory chain and cellular ATP depletion and a loss of mitochondrial transmembrane potential, resulting in cell death (Bates et al, 1994).Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, antipyretic, and analgesic properties. The molecular basis for the therapeutic effects of NSAIDs is the ability to inhibit cyclooxygenase (COX) activity and thereby suppress the production of prostaglandins (Vane, 1971).…”

MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death

“…In addition, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits complex I of the electron transport chain after being converted into its active metabolite 1-methyl-4-phenylpyridinium (MPP ϩ ) and results in a Parkinsonian phenotype in humans, non-human primates, and mice (6). As MPP ϩ -induced mitochondrial dysfunction leads to decreased production of ATP (7), cells attempt to meet their energy demand by enhancing the rate of glycolysis (8). Therefore, strategies to further increase the glycolytic rate could be exploited to sustain ATP production and slow the progression of neuronal degeneration in PD.…”