Hypoxemia Is Associated With Mitochondrial DNA Damage and Gene Induction
Implications for Cardiac Disease
- Marisol Corral-Debrinski, PhD;
- Georges Stepien, PhD;
- John M. Shoffner, MD;
- Marie T. Lott, MA;
- Kirk Kanter, MD;
- Douglas C. Wallace, PhD
- From the Departments of Genetics and Molecular Medicine (Drs Corral-Debrinski, Stepien, Shoffner, and Wallace and Ms Lott), Neurology (Drs Shoffner and Wallace), Biochemistry (Dr Wallace), Pediatrics (Dr Wallace), and Surgery (Dr Kanter), Emory University School of Medicine, Atlanta, Ga; Centre Cochin de Génétique Moleculaire, Paris, France (Dr Corral-Debrinski); and Centre National de la Recherche Scientifique, University of Paris-Sud, Orsay, France (Dr Stepien).
Abstract
Objective. —Oxidative phosphorylation (OXPHOS) deficiency due to hypoxemia or other causes was hypothesized to increase oxygen radical generation, damage mitochondrial DNA (mtDNA), and reduce adenosine triphosphate synthesis, resulting in compensatory OXPHOS gene induction. Therefore, we investigated the levels of mtDNA damage and OXPHOS transcripts in normal and ischemic hearts, and then in other forms of heart disease.
Design. —DNA was extracted from the heart and the levels of the common 4977 base pair mtDNA deletion were quantitated as an index for mtDNA damage. Total RNA was extracted from hearts and analyzed for OXPHOS transcript levels.
Results. —In control hearts, the 4977 base pair mtDNA deletion appeared at age 40 years and reached a maximum deletion of 0.0035%. Much higher levels were found in ischemic hearts (0.02% to 0.85%), as well as in three of 10 cases with other types of heart disease (0.017% to 0.16%). The OXPHOS transcripts were increased in all diseased hearts.
Conclusion. —Ischemic hearts have increased mtDNA damage and OXPHOS gene expression, suggesting that mtDNA damage is associated with OXPHOS deficiency. Oxidative phosphorylation defects may also play a role in some other forms of cardiac disease.
(JAMA. 1991;266:1812-1816)
Footnotes
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Reprint requests to Genetics and Molecular Medicine, 3031 Rollins Research Center, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, GA 30322 (Dr Wallace).
