Hibernation during Hypoxia in Cardiomyocytes
ROLE OF MITOCHONDRIA AS THE O2 SENSOR*
Abstract
During myocardial hibernation, decreases in coronary perfusion elicit inhibition of contraction, suggesting that energy demand is attenuated. We previously found an inhibition of contraction and O2 consumption during hypoxia (3% O2; PO2 = 20 torr for >2 h) in cardiomyocytes, which was reversible after reoxygenation. This study sought to determine whether mitochondria function as cellular O2 sensors mediating this response. Embryonic cardiomyocytes were studied under controlled O2 conditions. Hypoxia produced no acute decrease in mitochondrial potential as assessed using tetramethylrhodamine ethylester (TMRE). Cellular [ATP] was preserved throughout hypoxia, as assessed using the probe Magnesium Green. Thus, ATP synthesis and utilization remained closely coupled. Cells adapted to hypoxia for >2 h exhibited a 4% increase in mitochondrial potential upon reoxygenation, suggesting that a partial inhibition of cytochrome c oxidase had existed. To test whether the oxidase serves as an O2sensor, azide was administered (1 mm) to simulate the effects of hypoxia by lowering the V max of the oxidase. The effects of azide on contraction and mitochondrial potential mimicked the response to hypoxia. We conclude that partial inhibition of cytochrome oxidase during hypoxia allows mitochondria to function as the O2 sensor mediating the decreases in ATP utilization and O2 consumption during hypoxia.
Footnotes
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↵* This work was supported in part by National Institutes of Health NHLBI Grants HL32646 and HL35440.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by an American Heart Association Senior Fellowship Award.
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↵§ Supported by Societé Française d’Anesthesie Réanimation.
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↵¶ To whom correspondence should be addressed: Dept. of Medicine, The University of Chicago, MC6026, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-6790; Fax: 773-702-4736; E-mail:pschumac{at}medicine.bsd.uchicago.edu.
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↵1 The abbreviations used are: PCr, phosphocreatine; TMPD,N,N,N′,N′-tetramethyl-p-phenylenediamine; TMRE, tetramethylrhodamine ethylester; MgG, Magnesium Green; FCCP, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone; BDM, 2,3-butanedione monoxime.
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- Received October 20, 1997.
- Revision received November 12, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
