Mitochondrial dysfunction is a newly found group of inborn errors of metabolism in which there is a failure in the aerobic energy production. Disorders of mitochondrial metabolism exhibit a wide range of clinical symptoms which are related to the nature, severity and tissue distribution of the metabolic defect. Most reported cases are published in the neurological literature. In this report we describe for the first time a family with mitochondrial dysfunction with a high incidence of pre-eclampsia/eclampsia. The diagnosis of a mitochondrial disorder is verified by electronmicroscopic, electromyographic, histochemical and biochemical examinations. During pregnancy, the energy demand is increased due to both fetal and maternal requirements. A mitochondrial dysfunction, clinically symptomless in the non-pregnant state, may therefore become manifest during pregnancy. Characteristic features of pre-eclampsia such as disturbed ion transport, disturbed prostaglandin synthesis, vasoconstriction, platelet aggregation and hyperuricemia may be explained by mitochondrial dysfunction.

ExtractAn infant suffering from metabolic acidosis attributable to hyperlactatemia (6.1 mmol/liter) accompanied by hyperalaninemia (1 mmol/literj and hyperserinemia (0.6 mmol/literj is described. The urinary excretion of lactate and pyruvate was greatly elevated; the lactate to pyruvate ratio was normal. The urine showed low levels of citrate, isocitrate, and cis-aconitate, and low or normal levels of a-oxoglutarate, succinate, malate, and methylmalonate. Aspartate was slightly elevated in serum and urine, indicating a corresponding increase of its a-ketoacid oxaloacetate. These patterns of organic acids and amino acids suggested an in vivo defect in the oxidation of pyruvate. Fibroblasts cultured from skin biopsy from the patient metabolized radioactive pyruvate (final concentration 0.04-2 mmol/liter) to CO, at rates from 5 to 17% of that of fibroblasts from normal control subjects. Enzyme studies with fibroblast sonicates revealed a severe deficiency of the pyruvate dehydrogenase complex (about 8% of normal), and this error was localized to the first unit of the complex, i.e., the pyruvate dehydrogenase (about 4% of normal). Fibroblasts from both parents metabolized pyruvate to CO, at a slightly reduced rate, suggesting parental heterozygosity.

From 1986 to 1991, 472 muscle biopsy specimens from patients from different hospitals in Norway were examined. Of these, 364 were embedded for electron microscopy, and 194 were examined with electron microscopy. Ultrastructural alterations in the mitochondria were detected in 49 of these specimens. Characteristic electron microscopic findings included subsarcolemmal accumulation of abnormal mitochondria of various shapes and sizes, often containing electron-dense granules and sometimes lipid vacuoles in the mitochondria and diffusely electron-lucent matrix space. Paracrystalline inclusion bodies were seldom seen in specimens from young patients, but in some cases mitochondrial electron-dense granules at the cristae were found. These amorphous densities are consistent with lipoproteins, suggesting that they may represent an early stage of paracrystalline inclusions. Biochemical and genetic exploration of the patients with biopsy specimens suggesting mitochondrial disease indicated maternally genetic inheritance and an enzyme defect in the respiratory chain in 21 patients in two families. Three patients had MELAS syndrome, 7 Marinesco-Sjögren syndrome, and 2 Kearns-Sayre syndrome. Five family members had ptosis, cardiomyopathy, mild myopathy, and increased lactate in cerebrospinal fluid and serum. In addition to the diseases mentioned above, changes in the mitochondria were detected in other conditions such as Rett's syndrome (n = 1), ornithine transcarbamylase deficiency (n = 2), and hypothyroidism (n = 2) as well as in 3 patients with clinical and laboratory results indicative of inflammatory myopathy and 3 patients with clinical and laboratory findings consistent with peripheral neuropathy. It is concluded that, although ultrastructural changes in the mitochondria may represent unspecific findings, electron microscopic examination of muscle biopsy specimens is a useful screening method to select specimens for further biochemical analysis and to obtain an early and more precise diagnosis of the disease.

Glutathione plays an important role in drug resistance of tumor cells and in their ability to resist oxidative stress. Improved salvage of glutathione can be obtained through increased activity of γ‐glutamyltransferase (GGT), which is of importance in the maintenance of cellular glutathione homeostasis. We investigated the regulation of GGT in 2 cisplatin‐resistant and 1 cisplatin‐sensitive colon carcinoma cell lines. Enzyme activity was induced in all 3 cell lines after acute exposure to cisplatin. The elevation was significantly higher in sensitive cells (3.3‐fold) than in resistant (1.6‐ to 1.7‐fold) cells. Exposure of cells to oxidative stress generated by menadione also resulted in enzyme induction but only in cisplatin‐sensitive cells. Addition of anti‐oxidants had different effects on the 2 inductions: N‐acetylcysteine blocked the induction of both cisplatin and menadione, whereas catalase and glutathione‐ester blocked only the menadione induction. Glutathione depletion alone was not sufficient to induce GGT in these cells. The data show that GGT is regulated by multiple mechanisms during anti‐tumor drug treatment and oxidative stress and that reactive oxygen species were involved in the menadione, but not cisplatin, induction of the enzyme. Int. J. Cancer 88:464–468, 2000. © 2000 Wiley‐Liss, Inc.

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