Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

S. Hicks, N. Labinskyy, B. Piteo, D. Laurent, J. E. Mathew, S. A. Gupte, J. G. Edwards

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto- Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetesinduced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.

Original languageEnglish (US)
Pages (from-to)H903-H915
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number7
DOIs
StatePublished - Jun 10 2013

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Mitochondrial DNA
Type 2 Diabetes Mellitus
Heart Ventricles
Mutation
Oxidants
DNA Cleavage
Cardiac Myocytes
DNA Damage
Mitochondria
Diabetic Cardiomyopathies
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Glucose
Base Pairing
Doxorubicin
Myocardium
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hicks, S. ; Labinskyy, N. ; Piteo, B. ; Laurent, D. ; Mathew, J. E. ; Gupte, S. A. ; Edwards, J. G. / Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 304, No. 7. pp. H903-H915.
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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. / Hicks, S.; Labinskyy, N.; Piteo, B.; Laurent, D.; Mathew, J. E.; Gupte, S. A.; Edwards, J. G.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 304, No. 7, 10.06.2013, p. H903-H915.

Research output: Contribution to journalArticle

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