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PubMed1996

Assessment of the distribution of mitochondrial ribosomal RNA in melas and in thrombotic cerebral infarcts by in situ hybridization.

In situ hybridization to mitochondrial ribosomal RNA (rRNA) has been used to study the distribution of mitochondria in paraffin-embedded autopsy brain tissue from two patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and other organs from one of the patients. Comparison of in situ hybridization and electron microscopic findings in an antemortem biopsy specimen of pylorus from the latter patient showed a close correspondence between the distribution of hybridization signal on light microscopy and of mitochondria in ultrathin sections. Strong hybridization signal was present over smooth muscle fibres of the muscularis externa, which contained abnormal accumulations of mitochondria on electron microscopy. Hybridization to sections of skeletal muscle confirmed previous reports of 'ragged-red' fibres in this disorder and of mitochondrial accumulations in the walls of intramuscular blood vessels. To try to elucidate the role of vessel wall accumulation of mitochondria in the genesis of the stroke-like lesions, the distribution of mitochondrial rRNA was assessed in sections of brain from both of the cases of MFLAS and several cases of atherothrombotic cerebrovascular disease. Blood vessels in and adjacent to the cerebral lesions of MELAS showed strong hybridization signal with the mitochondrial probes, as was also seen in infarcts of various ages in the control brains. Only weak signal was present in the walls of blood vessels distant from the lesions, in both MELAS and control brains. These findings suggest that mitochondria accumulate in vascular endothelium and tunica media as a normal response to cerebral infarction or ischaemia. The accumulation of mitochondria in the cerebral lesions of MELAS may, at least in part, be a reaction to the destructive effects of the underlying metabolic dysfunction.

Brain↗

PubMed1994

Rapid increase in mitochondrial volume in nucleus magnocellularis neurons following cochlea removal.

Second-order auditory neurons in nucleus magnocellularis (NM) of the chick brainstem undergo a series of rapid metabolic changes following unilateral cochlea removal, culminating in the death of 25% of NM neurons. Within hours of cochlea removal, ipsilateral NM neurons show marked increases in histochemical staining for the mitochondrial enzymes succinate dehydrogenase and cytochrome oxidase. We investigated corresponding ultrastructural changes in NM neurons by preparing animals undergoing unilateral cochlea removal for transmission electron microscopy. We quantified changes in NM mitochondrial volume by stereological methods and qualitatively compared mitochondrial morphology between NM neurons destined to survive and those destined to die after cochlea removal. Within hours of cochlea removal, ipsilateral NM neurons show striking increases in mitochondrial volume (84% at 6 hours and 236% at 12 hours after cochlea removal compared to unoperated, control animals). At 2 week survival times, ipsilateral NM neurons contain fewer mitochondria than contralateral neurons. Surprisingly, anesthesia alone causes short-term increases in NM mitochondrial volume. Animals anesthetized with pentobarbital and ketamine and sacrificed 6 or 12 hours later showed a 45% increase in mitochondrial volume compared to previously unanesthetized animals. NM neurons destined to die within days of cochlea removal can be identified within several hours after deafferentation by the appearance of their ribosomes. We observed qualitative differences in mitochondrial morphology in dying neurons. Mitochondria in neurons destined to die consistently showed mitochondrial swelling and vacuolization indicative of metabolic dysfunction. Similar mitochondrial changes have been reported when mitochondria take up excess calcium. Ultrastructural changes in NM after cochlea removal display features of both programmed and pathological cell death, in which increased intracellular calcium is thought to play a role.

Anesthesia↗

PubMed1987

Aspirin disposition in rats acutely intoxicated with CCl4.

The profile of urinary salicylate metabolites was determined after an oral administration of acetylsalicylic acid (ASA) to: 1, control rats; 2, rats treated with CCl4 and 3, rats intoxicated with CCl4 and also pretreated with colchicine for 7 days. The following enzymatic activities were determined: liver and plasma ASA-esterase, liver UDP-glucuronyltransferase and liver aniline hydroxylase. The time course of plasma concentration of salicylates in similar groups were followed after the intraperitoneal administration of acetylsalicylic acid (ASA), salicylic acid (SA) or gentisic acid (GA). The animals acutely intoxicated with CCl4 showed a reduction in urinary excretion of glucuronates and an increased urinary excretion of gentisic and salicylic acids. The activities of plasma and liver ASA-esterases were significantly increased in CCl4-treated rats while the aniline hydroxylase was reduced and the UDP-glucuronyltransferase remained unchanged. The plasma half lives of salicylates were reduced in CCl4-treated rats regardless of the administered parent compound. Colchicine pre-treatment completely prevented the alterations produced by acute intoxication with CCl4. The heterogeneity of liver metabolic dysfunctions present in acute liver damage was evidenced. It is emphasized that the pharmacokinetic alterations produced by acute liver injury can be the result of complex factors that may involve changes in circulation, hepatic binding protein and other routes of elimination.

Animals↗

PubMed1975

Autoradiographic studies of nicotinic acid utilization in human-mouse heterokaryons and inhibition of utilization in newly-formed hybrid cells.

Although most mammalian cell lines can utilize either nicotinic acid or nicotinamide for the biosynthesis of nicotinamide adenine dinucleotide (NAD), thymidine kinase-deficient, mouse 3T3-4F cells are unable to utilize nicotinic acid. When 3T3-4E cells were fused with human D98/AH2 cells, autoradiography showed that the resultant heterokaryons synthesized NAD from nicotinic acid at rates comparable to the human parental cell. The rate of nicotinic acid utilization in heterokaryons remained unchanged over the four-day period of study following cell fusion. In contrast to the results observed with heterokaryons, nicotinic acid utilization was markedly reduced in hybrid cells. Of 100 hybrid clones examined at four or five days following cell fusion, 60 utilized nicotinic acid at rates less than one tenth that of the parental human cell. Similar results were observed in hybrid clones at nine or ten days following fusion. Uniformly high rates of NAD biosynthesis were observed in hybrid clones with nicotinamide as the precursor. This excludes the possibility that the reduction in nicotinic acid utilization in hybrid cells is due to a general metabolic dysfunction. The biochemical mechanism by which nicotinic acid utilization is markedly reduced has not been determined with certainty, however, several observations suggest genetic suppression.

Aminopterin↗

PubMedDate not supplied

Downregulation of complexin I and complexin II in the medial thalamus is blocked by N-acetylcysteine in experimental Wernicke's encephalopathy.

Metabolic dysfunction as a consequence of thiamine (vitamin B1) deficiency (TD), a model of Wernicke's encephalopathy, leads to elevation of extracellular glutamate concentration in vulnerable brain regions consistent with the development of excitotoxicity. Complexin I and complexin II are two genes labeling principally inhibitory and excitatory synapses, respectively. Because current evidence supports an important role for complexins in the modulation of neurotransmitter release, we examined the involvement of both proteins in the pathology of the medial thalamus and inferior colliculus in TD rats by immunoblotting. At the symptomatic stage, complexin I and complexin II levels in the medial thalamus were decreased by 63% and 45%, respectively, compared to control animals, but were unchanged in the inferior colliculus. These changes in thalamus were also observed using immunohistochemical methods, and seemed to be due to downregulation of both proteins because synaptophysin levels were unaffected in this brain region. In addition, cotreatment with the antioxidant N- acetylcysteine prevented both neuronal loss and downregulation of complexins. Our findings suggest dysregulation of excitatory and inhibitory neurotransmitter release in the medial thalamus, which is not present in the inferior colliculus. Furthermore, loss of complexin I and II in the thalamus may be mediated by processes that involve oxidative stress. Such changes in complexin levels may contribute to the pathophysiology of thalamic damage in TD, and offer a potential basis for the well-known differences in pathology between this structure and the inferior colliculus in this disorder.

Acetylcysteine↗

PubMed2003

Practice and principles of pharmacodynamic determination of HISS-dependent and HISS-independent insulin action: methods to quantitate mechanisms of insulin resistance.

Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50-60% of the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS-dependent and HISS-independent insulin action.

Animals↗

PubMed2000

Vertebrate mitochondrial DNA-a circle of surprises.

Evidence for the existence of a vertebrate mitochondrial genome first arose over 30 years ago. Application of emerging techniques of molecular biology established the structure of vertebrate mitochondrial DNA (mtDNA) as a small closed-circular species. The ability to purify these mtDNAs to a high degree facilitated studies on the overall replication and expression pattern of the genome. With the acquisition of the genomic sequences of human and mouse mtDNAs, it was possible to infer the genetic organization and some of the genes contained therein, as well as providing a basis for developing strategies to assign important regulatory elements involved in mtDNA replication and transcription. This, in turn, presented the opportunity to identify nucleus-encoded proteins that target to mtDNA and, in doing so, determine the replication and expression modes of the genome. Vertebrate cells, in general, need mtDNA due to the requirements for maintaining a functional oxidative phosphorylation pathway. Depression of mtDNA content or mutations in mtDNA can result in metabolic dysfunction severe enough, in some cases, to result in human lethality. The emergence of mouse models for human mitochondrial diseases should provide the experimental context to understand the full role of mtDNA in different cells, tissues, and organs; the control of organelle biogenesis; and the development of therapeutic strategies for treatment of mitochondrial disorders.

Animals↗

PubMed1999

Creatine and cyclocreatine attenuate MPTP neurotoxicity.

Systemic administration of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of the electron transport chain. Oral supplementation with creatine or cyclocreatine, which are substrates for creatine kinase, may increase phosphocreatine (PCr) or cyclophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neurons in the substantia nigra. Creatine and cyclocreatine had no effects on the conversion of MPTP to MPP+ in vivo. These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1995

Plasmodium berghei infection: dichloroacetate improves survival in rats with lactic acidosis.

The kinetics of Plasmodium berghei infection and the development of lactic acidosis, hypoglycemia, and anemia were defined in young Wistar rats. This model of metabolic dysfunction, which is similar to that of severe human malaria, was used to test the hypothesis that dichloroacetate, a treatment for lactic acidosis, prolonged survival in rats receiving a single antimalarial dose of quinine (20 mg/kg). Rats with hyperlactatemia (lactate > 5 mmol/liter, N = 183) were randomized to receive either dichloroacetate (100 mg/kg, N = 99) or saline (N = 84) and were monitored for outcome (survival or death) for 50 hr. Logistic regression modeling adjusting for baseline venous lactate concentration demonstrated that dichloroacetate increases survival rates in rats with venous lactate concentrations between 5 and 8.9 mmol/liter (odds ratio > 2.2, P < 0.021). This is the first demonstration that specific intervention to treat lactic acidosis can prolong survival and suggests that dichloroacetate may be useful as adjunctive therapy in the management of lactic acidosis complicating severe falciparum malaria.

Acidosis, Lactic↗

PubMed2002

Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13 gene: gene structure, tissue expression, and localization of the protein to peroxisomes.

Pex13 encodes an SH3-containing peroxisomal membrane protein required for the import of proteins into peroxisomes. In humans, mutations in PEX13 can disrupt peroxisome biogenesis and lead to peroxisomal metabolic dysfunction and neurodegenerative disease. We report here on the mouse gene Pex13 and its encoded protein. Mouse Pex13 spans 18 kb and consists of four exons. We detected Pex13 transcripts in all mouse tissues tested, with highest levels in liver and testis. The Pex13 open reading frame predicts a 44.5-kDa protein that displays 91% sequence identity to the human PEX13 protein. We have localized PEX13 protein to peroxisomes in mouse liver and show that this protein also sorts to peroxisomes in human skin fibroblasts. These data indicate that the structure and properties of the mouse and human PEX13 proteins are almost identical. We infer from these findings that targeted disruption of mouse Pex13 would provide an appropriate model for the study of PEX13 dysfunction in humans.

Amino Acid Sequence↗

PubMed2002

Expression of recombinant human betaine: homocysteine S-methyltransferase for x-ray crystallographic studies and further characterization of interaction with S-adenosylmethionine.

Elevated homocysteine as a result of dysfunctional metabolic enzymes is an independent risk factor for arteriosclerosis. Betaine:homocysteine S-methyltransferase (BHMT) (EC 2.1.1.5) is an important enzyme in the pathway of homocysteine metabolism in that it recycles methionine from homocysteine and nonfolate methyl donors. To initiate X-ray crystallographic structural studies, we created a BHMT expression construct for use in Escherichia coli that has a polyhistidine purification tag with no extraneous protein, usually found in commercial vectors, between the tag and protein sequence. The extra amino acids can hinder the crystallization process. A modified pET28b vector was designed to produce N-terminal polyhistidine-tagged proteins with a simple construction scheme having broad applicability because of the use of rare SapI cloning sites. BHMT expressed using this vector could be rapidly purified using metal chelate chromatography. Gel exclusion chromatography analysis showed that recombinant polyhistidine-tagged human BHMT is a tetramer. S-Adenosylmethionine (SAMe) has no effect on the recombinant BHMT's ability to methylate homocysteine nor does the enzyme appear to bind SAMe when examined by microcalorimetry.

Amino Acids↗

PubMed1990

Ischemia, reperfusion, and the determinants of tissue injury.

Much of the damage arising during ischemia and reperfusion can be attributed to the consequences of flow deprivation. However, while reperfusion is a prerequisite for the survival of tissue, it may have an injurious component, which, if counteracted, might enhance postischemic recovery. The complex and dynamic changes that occur during ischemia in the diseased human heart are difficult to model in experimental preparations. As a consequence, much remains to be learned about the identity and manipulability of cellular changes leading to irreversible injury. Although the subject of most studies, injury to the myocyte may not be the primary determinant of tissue injury and changes in the endothelium or vascular smooth muscle may play an important role. Once critical ischemia-induced cellular changes have been identified, interventions can be developed to delay their progression such that at the time of reperfusion more cells are potentially salvable. Suboptimal reperfusion may limit the recovery of the tissue through the induction of "reperfusion injury." Much controversy surrounds the importance and even the existence of this phenomenon. It is proposed that reperfusion injury may express itself in four distinct forms: a) reperfusion-induced arrhythmias, which are potentially lethal (but preventable or reversible) events occurring in otherwise viable tissue; b) myocardial stunning, which is expressed as prolonged (but eventually fully reversible) contractile and metabolic dysfunction; c) the induction of lethal injury in tissue that was potentially viable in the moments before reperfusion; d) accelerated necrosis in tissue that is already irreversibly injured (the "oxygen paradox"). All but the third of these categories has been shown to exist experimentally and clinically, and can be advantageously manipulated. Although it is likely that lethal reperfusion injury also exists, there is as yet no definitive proof. Clarification of this issue is of considerable importance to those undergoing angioplasty or thrombolytic procedures.

Animals↗

PubMed1991

Reperfusion-induced injury: a possible role for oxidant stress and its manipulation.

While some investigators recognize "reperfusion-induced injury" as an important component of the overall injury that occurs during ischemia and reperfusion, others question its existence. Resolution of this controversy is of considerable importance, particularly in an era of thrombolysis, since reperfusion-induced injury might be amenable to treatment. Although reperfusion is an absolute prerequisite for the recovery of ischemic tissue, it undoubtedly has some unfavorable effects. The identification of four (possibly sequential) components of reperfusion-induced injury helps to clarify the situation: a) Reperfusion after brief periods of ischemia can trigger arrhythmias in tissue that is potentially salvable; there is abundant experimental and clinical evidence for this form of reperfusion injury. b) Reperfusion may also be associated with "myocardial stunning"; however, given sufficient time, this prolonged postischemic contractile and metabolic dysfunction will recover. There is good experimental evidence and some clinical evidence for the existence of this type of reperfusion-induced injury. c) Reperfusion is commonly thought to cause lethal injury in cells that, until the time of reperfusion, were potentially salvable. However, conclusive evidence that reperfusion can kill cells does not yet exist. d) Reperfusion may alter the nature of necrotic processes in tissue that has already sustained lethal injury, while not altering the number of cells that die this may change the manner in which they die; this form of reperfusion injury could lead to differences in scar formation and vulnerability to aneurysm. There is considerable evidence for the existence of this form of reperfusion-induced injury. Many candidate mechanisms have been proposed for each form of reperfusion injury. Ionic disturbances (particularly for calcium) are often cited and, most recently, free radical-induced induced injury (oxidant stress) has been suggested as important. Considerable evidence exists that oxidant stress is involved in stunning and in reperfusion-induced arrhythmias, and characterization of underlying mechanisms might lead to novel therapeutic principles, such as antioxidant therapy. However, much remains to be learned.

Free Radicals↗

PubMed1994

Serum levels of the soluble receptor for tumor necrosis factor in patients with renal disease.

Tumor necrosis factor-alpha (TNF-alpha) has been found to be elevated in patients during hemodialysis and is thought to mediate some of the immune and metabolic dysfunctions in these patients. It has been speculated that infusions of soluble TNF receptor (sTNF-R) may prevent some of the cytotoxic effects of TNF. However, little is still known about preexisting serum TNF-R levels in patients with chronic renal failure, with or without hemodialysis. Therefore we analyzed serum samples of sTNF-R in 26 patients with chronic renal failure (group I), 61 hemodialysis patients (group II), 9 renal transplant recipients with acute renal failure requiring posttransplant dialysis (group III), 13 renal transplant patients with rejection and moderate kidney dysfunction (group IV), and 21 renal transplant recipients with borderline kidney dysfunction and diverse infectious complications (group V). Control groups consisted of 34 blood donors and diseased controls (11 renal transplant recipients with normal kidney function without complications). All patient groups showed significantly higher sTNF-R levels compared to the control groups. In groups I, IV, and V comparable levels were observed. In group I there was a clear correlation between sTNF-R levels and serum creatinine. The highest sTNF-R serum levels were seen in groups II and III, but there was no correlation with creatinine. In the posttransplant cases (group III and diseased controls) there was a decrease in sTNF-R with improvement of kidney function. These data strongly suggest that sTNF-R serum levels are dependent on kidney function.

Adult↗

PubMed1982

Brain lesions in a case of cystinosis.

Cystinosis usually spares the brain or causes only deposition of cystine crystals without destructive lesions in choroid plexus or, rarely, in brain parenchyma. A case of cystinosis is presented with unusually long survival and with bilateral necrosis, numerous concretions, and extensive demyelination of internal capsule and brachium pontis. No cystine crystals could be demonstrated in these lesions although they were present in the choroid plexus. The symmetry and unique distribution of the lesions as well as their histopathology suggested a progressive process caused by the metabolic dysfunction of cystinosis. The validity of this hypothesis will be determined by future experience as renal transplants enable more patients to survive into adult life.

Adult↗

PubMed1981

Mitochondrial alterations in the spinal ganglion neurons in ageing rats.

An ultrastructural study of the mitochondria was performed in the 3-, 24-, and 32-month-old rats. Accumulation of "unusual" substances or structures was the most striking characteristic in senescent neuron mitochondria. Tubular or filamentous inclusions, modifications in matrix density, deposit of glycogen particles and electron-dense globules were observed. The various nature of these alterations and their different situation in the cristae or in the matrix, suggested that they could be the result of some specific oxidative metabolism dysfunctions associated with ageing.

Aging↗

PubMed1987

Morphological observations in skeletal muscle from patients with a mitochondrial myopathy.

Mitochondrial metabolic dysfunction is considered to be the cause of certain congenital myopathies and a number of multisystem disorders in humans. The morphological hallmark of these diseases is the 'ragged red' fibre, which shows abnormally intensive oxidative enzyme reactions. Electron microscopy reveals that the numerically increased mitochondria in these fibres are often markedly enlarged and possess aberrant configurations of cristae. The mitochondrial matrix often contains lipid-like inclusions or shows vacuolation. The most characteristic mitochondrial abnormality is the occurrence of highly ordered inclusions in the intracristal or intermembrane space. These inclusions appear to be true crystals, composed of proteinaceous material. It is argued that the activity of accumulation of proteins in the mitochondria is related to the nuclear and nucleolar hypertrophy noticeable in the ragged red fibres. Since protein crystals in mitochondria in particular occur when an increased capillary density around the ragged red fibres is present, it is suggested that oxygen free radicals and lipid peroxidation processes are involved in the ragged red fibre pathology.

Crystallization↗

PubMed1988

New hypotheses on the pathogenesis and treatment of serous retinal detachment.

Recent experimental work has shown that, under normal conditions, most subretinal fluid is absorbed rapidly by active transport across the retinal pigment epithelium (RPE). However, in the presence of damage to the RPE blood-retinal barrier, subretinal fluid is rapidly cleared by passive forces. Thus, it is apparent that RPE defects do not by themselves cause serous retinal detachment. A hypothesis is presented that some serous detachments occur because normal metabolic transport systems of the RPE have been damaged, while the blood-retinal barrier remains intact to prevent passive drainage of the subretinal space. Under these conditions, a focal RPE "leak" can overload the system so that the serous fluid accumulates and persists. Photocoagulation of a leaking point can facilitate resolution of the fluid, but as long as the underlying metabolic dysfunction of the RPE persists, recurrence is possible. Some forms of serous detachment may thus be viewed as diffuse rather than focal ocular disorders in which the transport capability of the RPE has been damaged; such damage can result from systemic pathology such as adrenergic stress (e.g., central serous chorioretinopathy) or vascular disease (e.g., hypertension).

Animals↗