POLYAMINE MODULATION OF MITOCHONDRIAL CALCIUM-TRANSPORT - I - STIMULATORY AND INHIBITORY EFFECTS OF ALIPHATIC POLYAMINES, AMINOGLUCOSIDES AND OTHER POLYAMINE ANALOGS ON MITOCHONDRIAL CALCIUM-UPTAKE

In this study, the regulation of mitochondrial Ca2+ transport by polya mines structurally related to spermine and by analogous polycationic c ompounds was characterized. Similar to spermine, a number of amino gro ups containing cationic compounds exerted a dual effect on Ca2+ transp ort of isolated rat liver mitochondria: a decrease in Ca2+ uptake velo city and an enhancement of Ca2+ accumulation. In contrast to the effec ts of spermine and other aliphatic polyamines, however, the accumulati on-enhancing effect of aminoglu cosides, basic polypeptides, and metal -ammine complexes turned into an inhibition of Ca2+ accumulation at hi gher concentrations. Within groups of structurally related compounds, the potency to decrease Ca2+ uptake velocity and to enhance Ca2+ accum ulation correlated with the number of cationic charges. The presence o f multiple, distributed cationic charges was a necessary, but not suff icient criterion for effects on mitochondrial Ca2+ transport, because cationic polyamines and basic oligopeptides which did not enhance mito chondrial Ca2+ accumulation could be identified. Spermine was not able to antagonize the blocking of Ca2+ uptake by ruthenium red, but rathe r showed an apparent synergism, which can be explained as a displaceme nt of membrane-bound Ca2+ by spermine. The aminoglucosides, gentamicin and neomycin, but not the inactive polyamine bis(hexamethylene)-triam ine, inhibited the binding of spermine to intact mitochondria. Apparen tly, the binding of spermine, gentamicin, and a number of polyamine an alogues to low-affinity binding sites at mitochondria, which have low, but distinct structural requirements and which may correspond to phos pholipid headgroups, indirectly influences the activity state of the m itochondrial Ca2+ uniporter. The ability of aminoglucosides to displac e spermine from the mitochondria and to inhibit mitochondrial Ca2+ acc umulation may contribute to the mitochondrial lesions, which are known to occur early in the course of aminoglucoside-induced nephrotoxicity . (C) 1998 Elsevier Science Inc.