This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

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

JAMA. 1991;266(13):1812-1816.

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)

Author Affiliations
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).

Footnotes
Reprint requests to Genetics and Molecular Medicine, 3031 Rollins Research Center, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, GA 30322 (Dr Wallace).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

The pathophysiology of mitochondrial disease as modeled in the mouse
Wallace and Fan
Genes Dev. 2009;23:1714-1736.
ABSTRACT | FULL TEXT  

Mitochondrial Dysfunction in Atherosclerosis
Madamanchi and Runge
Circ. Res. 2007;100:460-473.
ABSTRACT | FULL TEXT  

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients
Fukushima and Fiocchi
Am. J. Physiol. Gastrointest. Liver Physiol. 2004;286:G804-G813.
ABSTRACT | FULL TEXT  

Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy
Lebrecht et al.
Circulation 2003;108:2423-2429.
ABSTRACT | FULL TEXT  

Mitochondrial DNA deletions in coronary artery bypass grafting patients
Levitsky et al.
Eur. J. Cardiothorac. Surg. 2003;24:777-784.
ABSTRACT | FULL TEXT  

Techniques and Pitfalls in the Detection of Pathogenic Mitochondrial DNA Mutations
Moraes et al.
J. Mol. Diagn. 2003;5:197-208.
ABSTRACT | FULL TEXT  

Quantification of Mitochondrial DNA Deletion, Depletion, and Overreplication: Application to Diagnosis
Chabi et al.
Clin. Chem. 2003;49:1309-1317.
ABSTRACT | FULL TEXT  

Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy
Zhang et al.
Cardiovasc Res 2003;57:147-157.
ABSTRACT | FULL TEXT  

Mitochondrial Integrity and Function in Atherogenesis
Ballinger et al.
Circulation 2002;106:544-549.
ABSTRACT | FULL TEXT  

A comparison of mitochondrial and nuclear DNA status in testicular sperm from fertile men and those with obstructive azoospermia
O'Connell et al.
Hum Reprod 2002;17:1571-1577.
ABSTRACT | FULL TEXT  

Mitochondrial Abnormalities in Ageing Macular Photoreceptors
Barron et al.
IOVS 2001;42:3016-3022.
ABSTRACT | FULL TEXT  

Impaired redox status and cytochrome c oxidase deficiency in patients with polymyalgia rheumatica
Chariot et al.
Ann Rheum Dis 2001;60:1016-1020.
ABSTRACT | FULL TEXT  

Decreased NADH dehydrogenase and ubiquinol-cytochrome c oxidoreductase in peripheral arterial disease
Brass et al.
Am. J. Physiol. Heart Circ. Physiol. 2001;280:H603-H609.
ABSTRACT | FULL TEXT  

Diabetes and Nutrition: The Mitochondrial Part
Berdanier
J. Nutr. 2001;131:344S-353.
ABSTRACT | FULL TEXT  

Mitochondrial Medicine - Molecular Pathology of Defective Oxidative Phosphorylation
Fosslien
Annals of Clinical & Laboratory Science 2001;31:25-67.
ABSTRACT | FULL TEXT  

Mitochondrial pathology in cardiac failure
Marin-Garcia et al.
Cardiovasc Res 2001;49:17-26.
FULL TEXT  

Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease
Brass et al.
Vasc Med 2000;5:225-230.
ABSTRACT  

The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method
Murdock et al.
Nucleic Acids Res 2000;28:4350-4355.
ABSTRACT | FULL TEXT  

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy
Jarreta et al.
Cardiovasc Res 2000;45:860-865.
ABSTRACT | FULL TEXT  

Mitochondrial DNA rearrangements in human oocytes and embryos
Barritt et al.
Mol Hum Reprod 1999;5:927-933.
ABSTRACT | FULL TEXT  

Nitric Oxide Modulates Mitochondrial Respiration in Failing Human Heart
Loke et al.
Circulation 1999;100:1291-1297.
ABSTRACT | FULL TEXT  

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients
Heddi et al.
J. Biol. Chem. 1999;274:22968-22976.
ABSTRACT | FULL TEXT  

Skeletal Muscle Mitochondrial DNA Injury in Patients With Unilateral Peripheral Arterial Disease
Bhat et al.
Circulation 1999;99:807-812.
ABSTRACT | FULL TEXT  

Detection of the `4977 bp' mitochondrial DNA deletion in human atherosclerotic lesions
Bogliolo et al.
Mutagenesis 1999;14:77-82.
ABSTRACT | FULL TEXT  

Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure
Lee et al.
J. Thorac. Cardiovasc. Surg. 1998;116:344-349.
ABSTRACT | FULL TEXT  

DNA Synthesis in Adult Feline Ventricular Myocytes : Comparison of Hypoxic and Normoxic States
Kozlovskis et al.
Circ. Res. 1996;78:289-301.
ABSTRACT | FULL TEXT  

Ischemic Delayed Neuronal Death : A Mitochondrial Hypothesis
Abe et al.
Stroke 1995;26:1478-1489.
ABSTRACT | FULL TEXT  

Cardiac Involvement in Mitochondrial Diseases, and Vice Versa
Williams
Circulation 1995;91:1266-1268.
FULL TEXT