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October 2, 1991, Vol 266, No. 13 >
ARTICLE | October 2, 1991

Hypoxemia Is Associated With Mitochondrial DNA Damage and Gene Induction: Title and subTitle BreakImplications for Cardiac Disease FREE

Marisol Corral-Debrinski, PhD; Georges Stepien, PhD; John M. Shoffner, MD; Marie T. Lott, MA; Kirk Kanter, MD; Douglas C. Wallace, PhD
[+] Author Affiliations

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


JAMA. 1991;266(13):1812-1816. doi:10.1001/jama.1991.03470130092035
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References

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)

REFERENCES

1 +
Shoffner JM, Wallace DC.  Oxidative phosphorylation diseases: disorders of two genomes.  In: Harris H, Hirschhorn K, eds. Advances in Human Genetics . New York, NY: Plenum Press; 1990;;19:267-330.
2 +
Torroni A, Stepien G, Hodge JA, Wallace DC.  Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes. J Biol Chem . 1990;;265:20 589-20 593.
3 +
Trounce I, Byrne E, Marzuki S.  Decline in skeletal muscle mitochondrial respiratory function: possible factor in aging. Lancet . 1989;;1:637-639.
4 +
Yen T-C, Chen Y-S, King K-L, Yeh S-H, Wei YH.  Liver mitochondrial respiratory functions decline with age. Biochem Biophys Res Commun . 1989;;165:994-1003.
5 +
Cortopassi GA, Arnheim N.  Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res . 1990;;18:6927-6933.
6 +
Hattori K, Tanaka M, Sugiyama S, et al.  Agedependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am Heart J . 1991;;121:1735-1742.
7 +
Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC.  Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A . 1989;;86:7952-7956.
8 +
Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S.  A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science . 1989;;244:346-349.
9 +
Ozawa T, Tanaka M, Sugiyama S, et al.  Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem Biophys Res Commun . 1990;;170:830-836.
10 +
Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD.  Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem . 1990;;54:823-827.
11 +
Parker WD Jr, Boyson SJ, Parks JK.  Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol . 1989;;26:719-723.
12 +
Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC.  Mitochondrial oxidative phosphorylation defects in Parkinson disease. Ann Neurol . In press.
13 +
Parker WD, Filley CM, Parks JK.  Cytochrome c oxidase deficiency in Alzheimer's disease. Neurology . 1990;;40:1302-1303.
14 +
Ikebe S- I, Tanaka M, Ohno K, et al.  Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence. Biochem Biophys Res Commun . 1990;;170:1044-1048.
15 +
Bandy B, Davison AJ.  Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Rad Biol Med . 1990;;8:523-539.
16 +
Richter C, Park J-W, Ames BN.  Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA . 1988;;85:6465-6467.
17 +
Piper HM, Sezer O, Schleyer M, Schwartz P, Hutter JF, Spieckermann PG.  Development of ischemia-induced damage in defined mitochondrial subpopulations. J Mol Cell Cardiol . 1985;;17:885-896.
18 +
Lochner A, Niekerk IV, Kotze JCN.  Mitochondrial acyl-CoA, adenine nucleotide translocase activity and oxidative phosphorylation in myocardial ischemia. J Mol Cell Cardiol . 1981;;13:991-997.
19 +
Kotaka K, Miyazaki Y, Ogawa K, Satake T, Sugiyama S, Ozawa T.  Reversal of ischemia-induced mitochondrial dysfunction after coronary reperfusion. J Mol Cell Cardiol . 1982;;14:223-231.
20 +
Rouslin W.  Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. Am J Physiol . 1983;;244:H743-H748.
21 +
Arroyo CM, Kramer JH, Leiboff RH, Mergner GW, Dickens BF, Weglicki WB.  Spin trapping of oxygen and carbon-centered free radicals in ischemic canine myocardium. Free Rad Biol Med . 1987;;3:313-316.
22 +
McCord JM.  Free radicals and myocardial ischemia: overview and outlook. Free Rod Biol Med . 1988;;4:9-14.
23 +
Otani H, Tanaka H, Inoue T, et al.  In vitro study on contribution of oxidative metabolism of isolated rabbit heart mitochondria to myocardial reperfusion injury. Circ Res . 1984;;55:168-175.
24 +
Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual . 2nd ed. New York, NY: Cold Spring Harbor Laboratory Press; 1989;.
25 +
Wallace DC, Zheng X, Lott MT, et al.  Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell . 1988;;55:601-610.
26 +
Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC.  Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell . 1990;;61:931-937.
27 +
Wilkinson L. SYSTAT: The System for Statistics . Evanston, Ill: SYSTAT Inc; 1989;.
28 +
Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC.  cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci U S A . 1987;;84:7580-7584.
29 +
Wallace DC, Ye J, Neckelmann SN, Singh G, Webster KA, Greenberg BD.  Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr Genet . 1987;;12:81-90.
30 +
Goto Y-I, Nonaka I, Horai S.  A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature . 1990;;348:651-653.

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1 +
Shoffner JM, Wallace DC.  Oxidative phosphorylation diseases: disorders of two genomes.  In: Harris H, Hirschhorn K, eds. Advances in Human Genetics . New York, NY: Plenum Press; 1990;;19:267-330.
2 +
Torroni A, Stepien G, Hodge JA, Wallace DC.  Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes. J Biol Chem . 1990;;265:20 589-20 593.
3 +
Trounce I, Byrne E, Marzuki S.  Decline in skeletal muscle mitochondrial respiratory function: possible factor in aging. Lancet . 1989;;1:637-639.
4 +
Yen T-C, Chen Y-S, King K-L, Yeh S-H, Wei YH.  Liver mitochondrial respiratory functions decline with age. Biochem Biophys Res Commun . 1989;;165:994-1003.
5 +
Cortopassi GA, Arnheim N.  Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res . 1990;;18:6927-6933.
6 +
Hattori K, Tanaka M, Sugiyama S, et al.  Agedependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am Heart J . 1991;;121:1735-1742.
7 +
Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC.  Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A . 1989;;86:7952-7956.
8 +
Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S.  A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science . 1989;;244:346-349.
9 +
Ozawa T, Tanaka M, Sugiyama S, et al.  Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem Biophys Res Commun . 1990;;170:830-836.
10 +
Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD.  Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem . 1990;;54:823-827.
11 +
Parker WD Jr, Boyson SJ, Parks JK.  Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol . 1989;;26:719-723.
12 +
Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC.  Mitochondrial oxidative phosphorylation defects in Parkinson disease. Ann Neurol . In press.
13 +
Parker WD, Filley CM, Parks JK.  Cytochrome c oxidase deficiency in Alzheimer's disease. Neurology . 1990;;40:1302-1303.
14 +
Ikebe S- I, Tanaka M, Ohno K, et al.  Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence. Biochem Biophys Res Commun . 1990;;170:1044-1048.
15 +
Bandy B, Davison AJ.  Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Rad Biol Med . 1990;;8:523-539.
16 +
Richter C, Park J-W, Ames BN.  Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA . 1988;;85:6465-6467.
17 +
Piper HM, Sezer O, Schleyer M, Schwartz P, Hutter JF, Spieckermann PG.  Development of ischemia-induced damage in defined mitochondrial subpopulations. J Mol Cell Cardiol . 1985;;17:885-896.
18 +
Lochner A, Niekerk IV, Kotze JCN.  Mitochondrial acyl-CoA, adenine nucleotide translocase activity and oxidative phosphorylation in myocardial ischemia. J Mol Cell Cardiol . 1981;;13:991-997.
19 +
Kotaka K, Miyazaki Y, Ogawa K, Satake T, Sugiyama S, Ozawa T.  Reversal of ischemia-induced mitochondrial dysfunction after coronary reperfusion. J Mol Cell Cardiol . 1982;;14:223-231.
20 +
Rouslin W.  Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. Am J Physiol . 1983;;244:H743-H748.
21 +
Arroyo CM, Kramer JH, Leiboff RH, Mergner GW, Dickens BF, Weglicki WB.  Spin trapping of oxygen and carbon-centered free radicals in ischemic canine myocardium. Free Rad Biol Med . 1987;;3:313-316.
22 +
McCord JM.  Free radicals and myocardial ischemia: overview and outlook. Free Rod Biol Med . 1988;;4:9-14.
23 +
Otani H, Tanaka H, Inoue T, et al.  In vitro study on contribution of oxidative metabolism of isolated rabbit heart mitochondria to myocardial reperfusion injury. Circ Res . 1984;;55:168-175.
24 +
Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual . 2nd ed. New York, NY: Cold Spring Harbor Laboratory Press; 1989;.
25 +
Wallace DC, Zheng X, Lott MT, et al.  Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell . 1988;;55:601-610.
26 +
Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC.  Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell . 1990;;61:931-937.
27 +
Wilkinson L. SYSTAT: The System for Statistics . Evanston, Ill: SYSTAT Inc; 1989;.
28 +
Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC.  cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci U S A . 1987;;84:7580-7584.
29 +
Wallace DC, Ye J, Neckelmann SN, Singh G, Webster KA, Greenberg BD.  Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr Genet . 1987;;12:81-90.
30 +
Goto Y-I, Nonaka I, Horai S.  A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature . 1990;;348:651-653.

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