Hans Nohl

Molecular basis of age-dependent changes in the activity of adenine nucleotide translocase ☆

(1) Rat-heart mitochondria from 30-month-old animals are 40% less active in translocating adenine nucleotides across the inner membrane than 3-month-old rats. (2) The number of sites available for binding the specific ligands to the adenine nucleotide carrier remains unchanged during aging. (3) The endogenous pool of the adenine nucleotides exhibits an age-dependent fall by more than 25%, essentially at the expense of ATP. The amount of ATP + ADP representing the exchangeable pool for adenine nucleotide translocation is decreased to the same extent. (4) Negatively charged phospholipids as well as polyunsaturated fatty acids of membrane lipids were found to be reduced with aging. (5) The results are discussed in terms of changes in the phospholipid-protein interactions due to the observed alterations in the physical state of the bulk phase of membrane lipids.

OH•-generation by adriamycin semiquinone and H2O2; An explanation for the cardiotoxicity of anthracycline antibiotics

Anthracycline-induced cardiomyopathy is still a matter of discussion. The many mechanisms proposed cannot explain a selective sensitivity of the heart to these antitumor drugs. The present paper provides experimental evidence which shows that heart tissue has special biochemical conditions which favour an anthracycline-catalysed electron shuttle to H2O2. This results in the generation of highly reactive OH.-radicals, instead of O-.2-radicals, which are expected to be formed in tissues also supplemented with anthracycline-activating microsomal enzyme systems.

Responses of mitochondrial superoxide dismutase, catalase and glutathione peroxidase activities to aging

The previous observation (Eur. J. Biochem., 82 (1978) 563--567) that age-dependent accumulation of lipid peroxides follows as a consequence of increased radical formation in mitochondria has prompted an examination of the response of a set of protective enzymes to the above situation. Levels of mitochondrial catalase activity as well as selenium-dependent glutathione peroxidase activity were found to be increased with age, while superoxide dismutase activity remained unchanged. No selenium-independent glutathione peroxidase activity could be detected either in preparations from young 3-month-old controls or in preparations from 2-year-old rats. Both the relatively high and unchanged levels of reduced glutathione and kinetic considerations suggest that glutathione peroxidase is preferentially involved in lipid peroxide metabolism, while catalase predominantly metabolizes mitochondrial H2O2.

Identification of free hydroxyl radicals in respiring rat heart mitochondria by spin trapping with the nitrone DMPO

Rat heart mitochondria have been observed to generate steady state concentrations of hydrogen peroxide and superoxide radicals [ 1,2]. We have indirect evidence that these oxygen species could give rise to the formation of OH’ radicals [2,3]. Support for this hypothesis comes from the observation that mitochondria stimulated to activate molecular oxygen [2,4] accumulate products of a reaction between membrane lipids and highly reactive oxygen species. Furthermore the existence of an OH’ radical generating pathway might be envisaged from the disappearance of mitochondrial HzOz in the presence of O;in RHM deficient in enzymes capable of destroying H,Oz 131. Since difficulties are encountered in the direct detection of oxy-radicals by ESR the method of spin trapping would seem well suited for the detection of these short-lived free radical species. However, using this technique, we observed that the physical identification of ESR spectra as definite spin adducts does not necessarily reflect the identity or the existence of free oxygen radicals in the medium. Therefore, this study was undertaken to establish criteria to determine whether ESR signals detected with 5,5’-dimethyl-lpyrroline-N-oxide (DMPO) may be attributed to the formation of free OH’ radicals in biological systems. Applying these criteria to rat heart mitochondria, it was found that these organelles were an active source of OH’ radicals, involving superoxide and hydrogen peroxide as precursors.

Age-Dependent Changes in the Structure-Function Correlation of ADP/ATP-Translocating Mitochondrial Membranes

Morphological changes in rat heart mitochondria following mobilization of the adenine nucleotide binding sites from the matrix to the cytosolic face of the inner membrane have been documented in this paper by means of electron microscopy. Significant differences in the shape of cristae membranes could be established when rat heart mitochondria from 3- and 30-month-old animals were compared. Changes in structural organization of the inner membrane - an event associated with the function of the adenine nucleotide carrier - were found to be distinctly less marked in mitochondria from the aged group. Kinetic analysis of this process revealed that both the velocity and the extent of conformational membrane changes were reduced as the animal ages. These observations are discussed in relation to the finding, also described in this paper, that aging is linked to a drastic decrease in the activity of adenosine diphosphate/adenosine triphosphate exchange.

Physiologische und pathophysiologische Bedeutung von Superoxid-Radikalen und die regulatorische Rolle des Enzyms Superoxiddismutase

SummaryThe monovalent reduction of molecular oxygen, resulting in the formation of superoxide radicals (

Influence of Mitochondrial Radical Formation on Energy‐Linked Respiration

O_{\dot 2}^ -

Kinetics of ADP, ATP transport in mitochondria as studied by the quench-flow method

) is regarded as to be an ongoing physiological process involved in the respiration and other biological processes of aerobic cells. These reactive oxygen species have been reported to function as cofactors in many biosynthetic reaction steps. Thus, deviations from cellular steady state concentrations may lead to a multiplicity of clinical symptoms or may to a great deal determine the characteristic of a distinct malady. Decrease of cellular