Biomedical subjects

M E Martens

Publications and source records attributed to M E Martens.

12 recordsLinked to original sources

PubMed1991

In vitro effects of glucocorticoid on mitochondrial energy metabolism.

A systematic study of the effects of the synthetic glucocorticoid, methylprednisolone (MP), on respiration and energy coupling in tightly-coupled mitochondria isolated from rat tissues has been initiated. In intact rat skeletal muscle, liver and heart mitochondria, incubation, in vitro, with greater than or equal to 0.1 mM MP caused inhibition of the state 3 respiratory rates with succinate and NAD-linked substrates. In skeletal muscle and heart mitochondria, the oxidation of succinate was significantly more sensitive to MP than was that of the NAD-linked substrates. No effects were seen at low concentrations (less than 0.02 mM) of MP. In all three tissues, these data together with analysis of the partial reactions of the electron transport chain and steady-state kinetic analysis of cytochrome reduction indicated that in isolated mitochondria high concentrations of MP: (a) inhibit the oxidation of NAD-linked substrates at the level of the respiratory chain between the primary NADH dehydrogenase flavoprotein and coenzyme Q, most likely at the iron-sulfur centers or coenzyme Q-binding proteins of complex I; and (b) inhibit succinate oxidation in intact (but not disrupted) mitochondria, not by inhibiting electron transfer along the respiratory chain, but possibly at the level of succinate transport into the mitochondria. The results of these studies suggest that the therapeutic effects of MP in mitochondrial disease result from indirect effects rather than direct effects on the mitochondrial membrane. More importantly, the absence of an effect at low MP concentrations provides the baseline information needed for further studies to be carried out in vivo.

Animals↗

PubMed1990

Heteroplasmy in chronic external ophthalmoplegia: clinical and molecular observations.

Chronic progressive external ophthalmoplegia (CPEO) describes a recognizable clinical syndrome frequently associated with variable dysfunction in other organ systems. Histochemical and biochemical studies suggested primary dysfunction of oxidative phosphorylation. This has recently been confirmed by demonstration of partially deleted as well as normal mitochondrial DNA--heteroplasmy--in some of these patients, most of them sporadic. In the six heteroplasmic CPEO patients that we have examined to date, the partially deleted species has been detected in all tissues tested, albeit in vastly different proportions. We report here detection of physiologically significant proportions of partially deleted mitochondrial DNA in several organs taken at autopsy from a CPEO patient with severe multisystem disease. We discuss the relationship of CPEO to several other clinical phenotypes associated with mitochondrial dysfunction, and discuss the possible implications of heteroplasmy for the development of variable phenotypes.

Child↗

PubMed1988

Kearns-Sayre syndrome: biochemical studies of mitochondrial metabolism.

Examination of oxidative metabolism in mitochondria isolated from quadriceps skeletal muscle biopsy specimens of 4 patients with Kearns-Sayre syndrome has shown that the mitochondria were tightly coupled, with maximal respiratory rates depending on the presence of adenosine diphosphate (ADP), Ca2+, or uncoupler. The state 3 respiratory rates with nicotinamide adenine dinucleotide (NAD)-linked substrates and succinate were much lower than those of control subjects. The cytochrome oxidase activities (measured with ascorbate + phenazine methosulfate as substrates) were also decreased, but this segment of the respiratory chain was not rate-limiting for succinate or NAD-linked substrate oxidation. Analyses of the steady-state reduction kinetics of the respiratory chain carriers revealed that the rate-limiting step of the impaired respiration with succinate or NAD-linked substrates lies between the c cytochromes and cytochrome oxidase. Measurement of the total substrate-reducible (at anaerobiosis) and chemically reducible levels of the cytochromes in mitochondria from 3 patients showed a severe deficiency of cytochrome a + a3 and an excess of the c cytochromes. To our knowledge, this is the first instance in which a mitochondrial electron transfer defect and cytochrome oxidase deficiency has been shown to be associated with an excess of the c cytochromes.

Adolescent↗

PubMed1988

Mitochondrial encephalomyopathies.

Mitochondrial encephalomyopathies are neurodegenerative disorders characterized by ragged-red myopathy and encephalopathy, which are recognized with increasing frequency. This article presents the clinical features; pertinent historical, biochemical, and genetic aspects; evaluation; and treatment of mitochondrial encephalomyopathies of childhood and the adult years.

Central Nervous System Diseases↗

PubMed1987

Generation of allantoin from the oxidation of urate by cytochrome c and its possible role in Reye's syndrome.

Allantoin in the presence of calcium ions has been implicated as a potential toxic agent in Reye's syndrome. An investigation of possible alternative sources of allantoin in humans, which lack the enzyme uricase, has been initiated. Urate is a strong reducing agent which can reduce cytochrome c nonenzymatically, with the concomitant production of CO2 and H+. The stoichiometries measured for the various reactants and products were 1 urate:2 cytochrome c:1 H+:1 CO2. The initial reaction rate depended on the concentrations of both urate and cytochrome c, with reaction kinetics that were first order with respect to urate and second order with respect to cytochrome c. The participation of molecular oxygen in this reaction could not be detected. The pH and ionic strength optima for this reaction were determined to be 9.5-10.5 and 10(-5) M, respectively. Based on the results reported here, the following balanced equation can be written: urate-2 + 2 cytochrome c+3 + 2 H2O----allantoin + 2 cytochrome c+2 + H+ + HCO3-. We propose that allantoin can be generated from the oxidation of urate by cytochrome c+3, and that this is a potential source of allantoin in human tissues.

Allantoin↗

PubMed1986

Reye's syndrome: mitochondrial swelling and Ca2+ release induced by Reye's plasma, allantoin, and salicylate.

The effects of Reye's plasma, allantoin, and salicylates on mitochondrial structure and Ca2+ transport have been investigated. Measurements of Ca2+ transport showed that when 20-30 microM Ca2+ was added to isolated rat liver mitochondria preincubated with one of these agents, Ca2+ uptake was followed by its spontaneous release into the medium. This was accompanied by large-amplitude swelling; the onset preceded the Ca2+ release. No further Ca2+ release was induced by uncoupler or the Ca2+ ionophore, A23187. The mitochondria continued to swell even after all of the Ca2+ had been released. The time between the addition of Ca2+ and the onset of swelling (or Ca2+ release) depended on the concentration of the agent added and the preincubation time; the extent of swelling did not. These effects were prevented, but not reversed, by ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, ruthenium red, rotenone, or adenine nucleotides. The massive swelling and membrane disruption were confirmed by electron microscopy of the treated vs untreated mitochondria. Similar results concerning swelling and Ca2+ release were also seen with Ca2+ alone, but the time scale was much longer (i.e., greater than 3-4 min), indicating that these agents act by potentiating Ca2+-induced alterations in mitochondrial structure, as suggested by our earlier work (T.Y. Segalman and C.P. Lee (1982) Arch. Biochem. Biophys. 214, 522-530; M.E. Martens and C.P. Lee (1984) Biochem. Pharmacol. 33, 2869-2876). Our data show, therefore, that allantoin, salicylates, and the "toxic" agent in Reye's plasma severely limit the ability of isolated rat liver mitochondria to maintain their structural integrity under conditions of limited Ca2+ loading.

Adenosine Diphosphate↗

PubMed1984

Reye's syndrome: salicylates and mitochondrial functions.

The effects of aspirin (acetylsalicylate, ASA) and related compounds in the presence of Ca2+ on the oxidative metabolism of isolated rat liver mitochondria were studied. Intact mitochondrial preparations preincubated with ASA + Ca2+ exhibited a transient stimulation of the state 4 respiratory rate with NAD+-linked substrates, followed by an inhibition which could not be released by the addition of ADP or uncoupler. Maximum respiratory rates were achieved by subsequent addition of NAD+ or succinate. The Ca2+-transport inhibitors ruthenium red and ethylene glycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA) prevented these effects. Five brands of commercial aspirin were tested and were as effective as purified ASA. Tylenol (acetaminophen) could reproduce these effects only at much higher (greater than or equal to 10-fold) concentrations. Other salicyl derivatives showed results qualitatively similar to ASA, with potencies in the order: acid much much greater than ASA much greater than alcohol greater than or equal to catechol greater than amide, salicylate being approximately 10-fold more potent than ASA. The magnitude of the effect seen depended on the Ca2+ (endogenous + exogenous) and salicylate concentrations/mg mitochondrial protein, and on the length of the preincubation. Added inorganic phosphate was also required. That salicylate + Ca2+ induces an increase in the permeability of the mitochondrial inner membrane was demonstrated by the observation that 90% of the intramitochondrial NAD(P)+ was released into the surrounding medium upon preincubation of intact mitochondria with these agents. Salicylate + Ca2+ had virtually no effect on respiration with succinate (+ rotenone) as substrate at salicylate concentrations which markedly affected NAD+-linked substrate oxidation. The presence of rotenone in the preincubation mixture prevented the damaging effects of salicylate + Ca2+ on the mitochondrial membrane, suggesting that the redox state of intramitochondrial pyridine nucleotides can modulate these effects. The results reported here are similar to those reported previously by our laboratory for the effects of Reye's plasma and allantoin + Ca2+, and indicate that, like these agents, salicylate and salicyl compounds can potentiate the Ca2+-induced damage to the mitochondrial inner membrane and may be another factor responsible for Reye's syndrome.

Animals↗

PubMed1980

Impaired substrate utilization in mitochondria from strain 129 dystrophic mice.

Mitochondria from skeletal muscle, heart and liver of strain 129/ReJ-dy dystrophic mice and their littermate controls were characterized with respect to their respiratory and phosphorylating activities. Skeletal muscle mitochondria from dystrophic mice showed significantly lower state 3 respiratory rates than controls with both pyruvate + malate and succinate as substrates (P less than 0.01). ADP/O and Ca2+/O ratios were found to be normal. A decreased rate of NADH oxidation (0.01 less than P less than 0.05) by sonicated mitochondrial suspensions from dystrophic mice was also seen. High respiratory rates with ascorbate + phenazine methosulfate as substrates indicated that cytochrome oxidase was not rate limiting in the oxidation of either pyruvate + malate or succinate. Skeletal muscle mitochondria from dystrophic mice showed no deficiency in any of the cytochromes or coenzyme Q. Mg2+-stimulated ATPase activity was higher in dystrophic muscle mitochondria than in controls, but basal and oligomycin-insensitive activities were virtually identical to those of controls. A significant reduction inthe intramitochondrial NAD+ content (0.01 less than P less than 0.02) was seen in dystrophic skeletal muscle as compared to controls. Heart mitochondria from dystrophic mice showed similar, though less extensive abnormalities while liver mitochondria were essentially normal. We concluded from these results that skeletal muscle mitochondria from strain 129 dystrophic mice possess impairments in substrate utilization which may result from (1) an abnormality in the transfer of electrons on the substrate side of coenzyme Q in the case of succinate oxidation; (2) a defect on the path of electron flow from NADH to cytochrome c, and (3) a deficiency of NAD+ in the case of NAD+-linked substrates.

Animals↗

PubMed1980

Fatty acid metabolism in skeletal muscle mitochondria from two strains of dystrophic mice.

Several aspects of fatty acids metabolism have been examined in skeletal muscle mitochondria from both strain 129 dystrophic (dy/dy) and myodystrophic (myd/myd) mice. Skeletal muscle mitochondria from dy/dy mice showed significantly decreased state 3 respiratory rates with both palmityl- and acetyl-carnitine + malate as substrates when compared with their normal littermate controls. A similar, though less severe impairment in acylcarnitine oxidation by mitochondria from myd/myd skeletal muscle has also been shown by us in a previous study. In the present study, kinetic measurements revealed decreased activities of the reverse carnitine palmityltransferase (palmitylcarnitine + CoASH as substrates) in intact mitochondria from dy/dy muscle, and of citrate synthase in myd/myd muscle mitochondria. However, neither of these reactions appeared to be rate limiting for acylcarnitine oxidation in mouse skeletal muscle mitochondria. All other enzyme activities of cofactor contents measured were either comparable to those of controls or were higher. The results reported here indicate that neither of the impairments in acylcarnitine oxidation by skeletal muscle mitochondria from dy/dy or myd/myd mice is due to deficiencies in either carnitine palmityltransferase, carnitine acetyltransferase, citrate synthase, coenzyme A, or substrate-reducible flavoprotein.

Acetylcarnitine↗

PubMedDate not supplied

Defective oxidative metabolism of myodystrophic skeletal muscle mitochondria.

A small-scale procedure for preparing tightly coupled intact skeletal muscle mitochondria from myodystrophic (myd/myd) mice is described. Mitochondrial preparations derived from heart, liver, and skeletal muscle of myd/myd and their littermate (+/?) controls are characterized with respect to their cytochrome content and their oxidative and phosphorylative capacities. Our data indicate that there is an impairment in the NADH CoQ region of the respiratory chain of myodystrophic skeletal muscle mitochondria. Both heart and liver mitochondria of myd/myd exhibited normal activities of respiratory chain-linked oxidative phosphorylation.

Adenosine Diphosphate↗

PubMedDate not supplied

Impaired NADH-CoQ reductase activity in a child with moyamoya syndrome.

A 33-month-old boy with recurrent stroke-like episodes had angiographic features characteristic of moyamoya syndrome. Mitochondrial encephalomyopathy was suspected because of lactic acidosis and ptosis. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed impairment of NADH-coenzyme Q reductase activity. Mitochondrial metabolic disorders may cause moyamoya syndrome when other known associated factors are absent.

Arterial Occlusive Diseases↗

PubMedDate not supplied

Partial cytochrome b deficiency and generalized dystonia.

An 18-year-old female had clinical features of idiopathic torsion dystonia with bilateral hypodense putaminal lesions on computed tomography. Mitochondrial encephalomyopathy was suspected because of persistent lactic acidemia and myopathy. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed partial cytochrome b deficiency indicating a defect in the cytochrome b- c1 complex. This finding represents a unique, multisystem syndrome of progressive dystonia, putaminal degeneration, myopathy, and mitochondrial cytochrome b deficiency. Mitochondrial metabolic disorders may be a cause of torsion dystonia when other known associated factors are absent.

Adolescent↗