Therapy of mitochondrial disorders

Przyrembel, Hildegard

doi:10.1007/bf01812853

Cited by 92 publications

(28 citation statements)

References 38 publications

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“…After that, when the drugs are known to be safe (several of them are already tested in other patients), they can be tested on patients with defects in oxidative phosphorylation. Of course together with other treatments that proved valuable in individual patients [20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Untitled

Scholte

Ross

et al. 1997

Molecular and Cellular Biochemistry

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We modified the isolation procedure of muscle and heart mitochondria. In human muscle, this resulted in a 3.4 fold higher yield of better coupled mitochondria in half the isolation time. In a preparation from rat muscle we studied factors that affected the stability of oxidative phosphorylation (oxphos) and found that it decreased by shaking the preparation on a Vortex machine, by exposure to light and by an increase in storage temperature. The decay was found to be different for each substrate tested. The oxidation of ascorbate was most stable and less sensitive to the treatments.When mitochondria were stored in the dark and the cold, the decrease in oxidative phosphorylation followed first order kinetics. In individual preparations of muscle and heart mitochondria, protection of oxidative phosphorylation was found by adding candidate stabilizers, such as desferrioxamine, lazaroids, taurine, carnitine, phosphocreatine, N-acetylcysteine, Trolox-C and ruthenium red, implying a role for reactive oxygen species and calcium-ions in the in vitro damage at low temperature to oxidative phosphorylation.In heart mitochondria oxphos with pyruvate and palmitoylcarnitine was most labile followed by glutamate, succinate and ascorbate. We studied the effect of taurine, hypotaurine, carnitine, and desferrioxamine on the decay of oxphos with these substrates. 1 mM taurine (n = 6) caused a significant protection of oxphos with pyruvate, glutamate and palmitoylcarnitine, but not with the other substrates. 5 mM L-carnitine (n = 6), 1 mM hypotaurine (n = 3) and 0.1 mM desferrioxamine (n = 3) did not protect oxphos with any of the substrates at a significant level.These experiments were undertaken in the hope that the in vitro stabilizers can be used in future treatment of patients with defects in oxidative phosphorylation. (Mol Cell Biochem 174: 61-66, 1997)

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Section: Discussionmentioning

confidence: 99%

Untitled

Scholte

Ross

et al. 1997

Molecular and Cellular Biochemistry

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“…Encouraging results have been described in some patients with complex I deficiency (Wijburg et al, 1989) and complex III deficiency (Eleff et al, 1984) but in other patients no improvement was observed at all (Przyrembel, 1987).…”

Section: Resultsmentioning

confidence: 93%

Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

Wijburg

Groot

Feller

et al. 1991

J of Inher Metab Disea

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In recent years a large number of patients with different clinical phenotypes due to inborn defects in one or more of the mitochondrial respiratory chain enzyme complexes have been described. Much interesting and exciting work has been done to improve the diagnostic procedures and to elucidate the biochemical and genetic backgrounds of these diseases. However, the results of treatment of patients with a defect in the respiratory chain are often disappointing and difficult to evaluate because of the episodic course of the various diseases.In order to determine the potential value of a new in vitro method for studying the effects of possible therapeutic agents for respiratory chain defects, we studied the effects of menadione (vitamin K 3, 2-methyl-l,4-naphthoquinone) on complex I (NADH:Q1 oxidoreductase) and complex III (CoQ: cytochrome c oxidoreductase) deficient fibroblasts. MATERIALS AND METHODSFibroblasts were cultured from skin biopsies of healthy controls and used after reaching confluency. Lactate and pyruvate production was measured after 4h incubation with 5 mmol/L glucose as previously described (Wijburg et al., 1990). ATP concentration in fibroblasts was measured after 4h incubation at 37°C in KrebsHenseleit bicarbonate buffer with 5mmol/L pyruvate, fortified with 20mmol/L HEPES. The incubation was stopped by the addition of 5 mol/L perchloric acid. After 30min at 4°C the fibroblasts were scraped out of the culture flask using a rubber policeman. The fluid was removed and centrifuged at 4°C to remove denatured protein. 500 #1 of the protein-free acid extract was neutralized to pH 6-7 using 112 #1 of neutralizing buffer (2mol/L KOH, 0.6mol/L MOPS) and centrifuged at 15 000g at 4°C. ATP was measured fluorimetrically in the acid-free extract.For inhibition of complex I, 25 gmol/L of rotenone was added to the incubation medium. Complex III was inhibited by the addition of 18 #mol/L antimycin. Complex IV (cytochrome c oxidase) was inhibited by 5 mmol/L sodium azide in the incubation medium. Menadione (Janssen Chimica, Beerse, Belgium) was added to the incubation medium at a concentration of 5/~mol/L. 293

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“…If a bioenergetic defect underlies neurodegeneration in Parkinson's disease, therapeutic interventions which ameliorate or bypass the metabolic defect might have a protective effect (Beal, 1992;Przyrembel, 1987). Such approaches might include: i) vitamins such as thiamine, riboflavine and biotin which are coenzymes of respiratory chain enzymes; ii) compounds such as vitamin C or vitamin K3 (menadione) to bridge a defect in electron transport; iii) the use of coenzyme Q-10 as an electron acceptor or donor; and iv) N-acetyl carnitine which has the potential to shunt oxidative metabolism down stream from complex I.…”

Section: Mitochondrial Defectsmentioning

confidence: 99%

A scientific rationale for protective therapy in Parkinson's disease

Olanow

1993

J. Neural Transmission

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The desire to introduce neuroprotective therapy for Parkinson's disease has begun to focus attention on pathogenetic mechanisms responsible for cell death. Considerable theory and some evidence have now accumulated to suggest that factors related to oxidative stress, mitochondrial bioenergetic defects, excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies acting either singularly or in combination may contribute to the development of cell death in Parkinson's disease. A better understanding of the specific pathogenetic mechanism involved in cell degeneration might provide a scientific basis for testing a putative neuroprotective therapy. This chapter reviews the theory and evidence in support of these different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease.

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Therapy of mitochondrial disorders

Cited by 92 publications

References 38 publications

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Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

A scientific rationale for protective therapy in Parkinson's disease

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