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003 OCoLC;

005 20131120121714.0;

006 m o d ;

007 cr bn|||||||||;

008 130904s2013 ncua ob 000 0 eng d;

035 a| (Sirsi) o857589990;

035 a| (OCoLC)857589990;

049 a| EREE;

090 a| QD181.O1;

100 1 a| Fisher-Wellman, Kelsey H.,e| author.?| UNAUTHORIZED;

245 10 a| Establishment of the pyruvate dehydrogenase complex as a central regulator of mitochondrial redox within skeletal muscle /c| Kelsey H. Fisher-Wellman.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2013.;

300 a| 104 pages :b| illustrations (some color);

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 5.58Mb2| rda;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2013.;

500 a| Presented to the faculty of the Department of Kinesiology.;

500 a| Advisor: P. Darrell Neufer.;

500 a| Title from PDF t.p. (viewed September 18, 2013).;

520 3 a| Once regarded as "byproducts" of aerobic metabolism, the production of superoxide/H₂O₂ is now understood to be a highly specialized and extensively regulated process responsible for exerting control over a vast number of thiol-containing proteins, collectively referred to as the redox-sensitive proteome. Although disruptions within this process, secondary to elevated peroxide exposure, have been linked to disease, delineation of the sources and mechanisms regulating this increased peroxide burden remain poorly defined and as such difficult to target using pharmacotherapy. Herein we demonstrate a role for pyruvate dehydrogenase (PDH) as a key source of H₂O₂ under physiological constraints in which respiratory chain-dependent electron leak is negligible. PDH is shown to generate H₂O₂ as a function of glutathione content, matrix metabolic balance, as well as antioxidant reductase activity. With respect to the latter, manipulation of matrix redox buffering reveals a novel mechanism whereby H₂O₂ producing NADH-linked dehydrogenases, such as PDH, are functionally linked to the redox buffering network within skeletal muscle through the activity of nicotinamide nucleotide transhydrogenase (NNT). These findings highlight the importance of NNT and the entire redox buffering system in regulating cytosolic peroxide emission and suggest a novel and pivotal role for PDH as a redox-sensitive reporter of matrix redox buffering integrity and nutrient status.;

504 a| Includes bibliographical references.;

650 0 a| Superoxides.=| ^A801124;

650 0 a| Proteomics.=| ^A566733;

650 0 a| Pyruvates.=| ^A1172402;

650 0 a| Oxidation-reduction reaction.=| ^A220362;

653 a| Physiology;

653 a| Biochemistry;

700 1 a| Neufer, P. Darrell,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Kinesiology.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/4236;

949 o| jgml;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 3361957;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3361957-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 9/4/2013x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3361957-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 9/4/2013x| ETDz| HERESOURCE;

Establishment of the pyruvate dehydrogenase complex as a central regulator of mitochondrial redox within skeletal muscle / Kelsey H. Fisher-Wellman.

Author/creator	Fisher-Wellman, Kelsey H. author.
Other author	Neufer, P. Darrell, degree supervisor.
Other author	East Carolina University. Department of Kinesiology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2013.
Description	104 pages : illustrations (some color)
Supplemental Content	Access via ScholarShip
Subjects	Superoxides. Proteomics. Pyruvates. Oxidation-reduction reaction.

Summary	Once regarded as "byproducts" of aerobic metabolism, the production of superoxide/H₂O₂ is now understood to be a highly specialized and extensively regulated process responsible for exerting control over a vast number of thiol-containing proteins, collectively referred to as the redox-sensitive proteome. Although disruptions within this process, secondary to elevated peroxide exposure, have been linked to disease, delineation of the sources and mechanisms regulating this increased peroxide burden remain poorly defined and as such difficult to target using pharmacotherapy. Herein we demonstrate a role for pyruvate dehydrogenase (PDH) as a key source of H₂O₂ under physiological constraints in which respiratory chain-dependent electron leak is negligible. PDH is shown to generate H₂O₂ as a function of glutathione content, matrix metabolic balance, as well as antioxidant reductase activity. With respect to the latter, manipulation of matrix redox buffering reveals a novel mechanism whereby H₂O₂ producing NADH-linked dehydrogenases, such as PDH, are functionally linked to the redox buffering network within skeletal muscle through the activity of nicotinamide nucleotide transhydrogenase (NNT). These findings highlight the importance of NNT and the entire redox buffering system in regulating cytosolic peroxide emission and suggest a novel and pivotal role for PDH as a redox-sensitive reporter of matrix redox buffering integrity and nutrient status.
General note	Presented to the faculty of the Department of Kinesiology.
General note	Advisor: P. Darrell Neufer.
General note	Title from PDF t.p. (viewed September 18, 2013).
Dissertation note	Ph.D. East Carolina University 2013.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Establishment of the pyruvate dehydrogenase complex as a central regulator of mitochondrial redox within skeletal muscle / Kelsey H. Fisher-Wellman.

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