Regulation and role of the mitochondrial transcription factor in the diabetic rat heart.
To clarify the mechanism of abnormalities in mitochondrial expression and function in diabetic rat heart, we have studied the transcriptional activities of mitochondrial DNA using isolated intact mitochondria from the heart of either diabetic or control rats. The transcriptional activity of cardiac mitochondria isolated from diabetic rats decreased to 40% of the control level (P < 0.01). Consistently, in the heart of diabetic rats, the content of cytochrome b mRNA encoded by mitochondrial DNA was reduced to 50% of control (P < 0.01). This abnormal transcriptional activity of mitochondrial DNA could not be explained by mRNA or protein contents of mitochondrial transcription factor (mtTFA), but mtTFA binding to the promoter sequence of mitochondrial DNA, assessed by gel-shift assay, was attenuated in diabetic rats. In contrast, the mRNA expression of nuclear-encoded mitochondrial genes, such as ATP synthase-beta, was not affected by diabetes. Although O(2) consumption of the mitochondria from diabetic rats was decreased, H(2)O(2) production in these rats was increased compared with the control. Insulin treatment reversed all the abnormalities found in diabetic rats. These results clearly indicate that an impairment of binding activity of mtTFA to the promoter sequence has a key role in the abnormal mitochondrial gene expression, which might explain the mitochondrial dysfunction found in diabetic heart.
Nishio
Yoshihiko
Y
Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. nishio@belle.shiga-med.ac.jp
Kanazawa
Akio
A
Nagai
Yoshio
Y
Inagaki
Hidetoshi
H
Kashiwagi
Atsunori
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045303:Cytochromes b / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D008297:Male; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D001786:Blood Glucose; D004272:DNA, Mitochondrial; C489030:Tfam protein, rat; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D045303:Cytochromes b; C412204:ATP synthase subunit 6; D025261:Mitochondrial Proton-Translocating ATPases