Aminoglycoside antibiotics achieve bacterial killing by binding to bacterial ribosomes and inhibiting protein synthesis. To examine whether similar mechanisms could be present in renal tubular cells prior to the onset of overt proximal tubular necrosis due to these drugs, we isolated microsomes from Fischer rats given 20 mg/kg gentamicin every 12 h subcutaneously for 2 days and from vehicle-injected controls. Concomitant studies of renal structure, function, and mitochondrial respiration were carried out. [3H]leucine incorporation into renal microsomes of treated animals was reduced by 21.9% (P less than 0.01), whereas brain and liver microsomes from the same animals were unaffected. Gentamicin concentration in the renal microsomal preparation was 56 micrograms/ml, a value 7- to 10-fold above concentrations necessary to inhibit bacterial growth. Conventional renal function studies were normal (blood urea, serum creatinine, creatinine clearance). Treated animals showed only a mild reduction of inulin clearance, 0.71 compared with 0.93 ml.min-1.100 g-1 in controls (P less than 0.05), and an increase in urinary excretion of N-acetylglucosaminidase of 20 compared with 14.8 units/l (P less than 0.05). Renal slice transport of p-aminohippuric acid, tetraethylammonium, and the fractional excretion of sodium were well preserved. There was no evidence, as seen by light microscopy, of proximal tubular necrosis. Mitochondrial cytochrome concentrations were normal and respiratory activities only slightly reduced. Processes similar to those responsible for bacterial killing could be involved in experimental gentamicin nephrotoxicity before overt cellular necrosis.
Mitochondria contain four distinct compartments and a selectively permeable inner membrane. These compartments provide an important means of regulation of mitochondrial activity via various carrier and translocase activities. Nutritional substrates derived from glucose, fatty acids, and branched chain amino acids are utilized by mitochondria in a tightly controlled manner. This control is provided by the specific dehydrogenase enzymes and carnitine related reactions and is dependent on cellular needs for energy and availability of various substrates. Several possible in vivo controllers of mitochondrial respiration exist. In this review we have examined: the dependence of mitochondrial function on oxygen availability, the cellular phosphate potential, and the adenine nucleotide translocase activity; the role of adenosine as the regulator of coronary flow providing a link to mitochondrial metabolism; the importance of the creatine-phosphate shuttle and the existence of separate mitochondrial and myofibrillar creatine-kinase enzymes; and the physiologically important mechanisms of the regulation of mitochondrial metabolic activity in the heart.
ABSTRACT. Development of the mitochondrial antioxidant defense system was studied to assess its potential role in the newborn mammal's tolerance to oxidative challenge and to gain insight into the fetal adaptation to a relatively hyperoxic adult environment. Isolated heart, kidney, and liver mitochondria from fetal, newborn, and adult guinea pigs were used. In situ function of the antioxidant enzymes was estimated in mitochondrial suspensions after the addition to selenite or tert-butyl hydroperoxide by determining NAD(P)H oxidation rates spectrophotometrically at 340-375 nm. Kidney and liver mitochondria from newborn animals were less susceptible to selenite and tert-butyl hydroperoxide-induced NAD(P)H oxidation. The pattern of change, however, varied widely with tissue type. Kidney mitochondria displayed the largest change with a 3-to 4-fold increase in rate from the fetal to adult period. NAD(P)H oxidation rates in intact mitochondria did not correlate consistently with glutathione reductase and peroxidase activities in sonicated mitochondria suggesting in situ regulation by other endogenous factors. Immediately after birth, mitochondrial glutathione reductase and peroxidase activities dropped 38-50% and 50-70%, respectively, in all tissues studied. Total glutathione content of heart and liver mitochondria did not change with age. Adult kidney mitochondrial glutathione, however, declined to 24% of fetal values. Mitochondrial superoxide dismutase activity increased 150-300% from the fetal to the adult period in all tissues studied. Perinatal changes in the mitochondrial antioxidant system and their relationship to mitochondrial calcium metabolism are discussed in terms of the newborn's resistance to oxidative stress. (Pediatr Res 26:220-226, 1989) Abbreviations GSH, reduced glutathione GSSG, oxidized glutathione SOD, manganese superoxide dismutase tBOOH, tert-butyl hydroperoxide Mammalian birth introduces a dramatic environmental change on the emerging organism. Altered circulation and oxygen availability necessitate adaptive changes in metabolism. Before birth, fetal oxygen tensions (Pao2) are low (25 mm Hg). After birth, average Pao2 rises (to 80-90 mm Hg) initiating the switch to a more aerobic metabolism (1-4). In the newborn
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