Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus.
Screening subtraction libraries from normal and type II diabetic human skeletal muscle, we identified four different mitochondrially encoded genes which were increased in expression in diabetes. The genes were cytochrome oxidase I, cytochrome oxidase III, NADH dehydrogenase IV, and 12s rRNA, all of which are located on the heavy strand of the mitochondrial genome. There was a 1.5- to 2.2-fold increase in the expression of these mRNA molecules relative to total RNA in both type I and type II diabetes as assessed by Northern blot analyses. Since there was approximately 50% decrease in mitochondrial DNA copy number as estimated by Southern blot analyses, mitochondrial gene expression increased approximately 2.5-fold when expressed relative to mitochondrial DNA copy number. For cytochrome oxidase I similar changes in mitochondrial gene expression were observed in muscle of nonobese diabetic and ob/ob mice, models of type I and type II diabetes, respectively. By contrast there was no change or a slight decrease in expression of cytochrome oxidase 7a, a nuclear-encoded subunit of cytochrome oxidase, and the expression of mitochondrial transcription factor 1 in human skeletal muscle did not change with type I or type II diabetes. The increased mitochondrial gene expression may contribute to the increase in mitochondrial respiration observed in uncontrolled diabetes.
Antonetti
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DA
Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215.
Reynet
C
C
Kahn
C R
CR
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D018628:Gene Dosage; D005786:Gene Expression Regulation; D015723:Gene Library; D006609:High Mobility Group Proteins; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000502:physiology*; D009245:NADH Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D013311:Streptozocin / Q000494:pharmacology; D014018:Tissue Distribution; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; C499631:TFAM protein, human; C081930:Tfam protein, mouse; C489030:Tfam protein, rat; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D013311:Streptozocin; D012313:RNA; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV