OXIDANT-MEDIATED REPRESSION OF MITOCHONDRIAL TRANSCRIPTION IN DIABETIC RATS

Diabetes-associated mitochondrial dysfunction is recognized, but the u nderlying mechanisms are unknown. Using isolated liver mitochondria fr om streptozotocin-induced diabetic Sprague-Dawley rats, we showed that diabetes can result in a > 95% loss in mitochondrial transcriptional capacity. Decreased transcription correlated well with both disease st atus, as indicated by serum lipemia and ketone levels, and with increa sed resistance of the mitochondrial transcription system to oxidative stress imposed by the hydrophilic AAPH [2,2'-azobis-(2-amidinopropane) hydrochloride] or the hydrophobic AMVN [2,2'-azobis-(2,4,-dimethyl-val eronitrile)]. The onset of AAPH- or AMVN-induced lipid peroxidation wa s also delayed; this suggests that liver mitochondrial membranes from diabetics have increased resistance to peroxyl radical-mediated lipid peroxidation. Lipid peroxidation induced endogenously was increased, h owever, suggesting a state of increased oxidative stress likely exists in vivo. Furthermore, changes in the rate of lipid peroxidation occur ring during the propagation phase were also affected by diabetes. This implies possible changes in lipid composition or structure. Analysis indicated that the factors protecting mitochondria from lipid peroxida tion differ from those involved in protecting the transcription system , and that both are independent of free radical scavenger levels. Thes e results suggested that diabetes alters mitochondrial exposure and/or response to reactive species and provided clues to the role of oxidan t stress in the development of diabetes-associated mitochondrial dysfu nction. Copyright (C) 1997 Elsevier Science Inc.