title: Potentially diagnostic electron paramagnetic resonance spectra elucidate the underlying mechanism of mitochondrial dysfunction in the deoxyguanosine kinase deficient rat model of a genetic mitochondrial DNA depletion syndrome.
abstract: A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool.
authors.affiliation: National Biomedical EPR Center, Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: brian.bennett@mu.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Bennett
authors.affiliation: Human Molecular Genetics Center and Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: dhelbling@mcw.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Helbling
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: hmeng@mcw.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: jjarzemb@mcw.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Jarzembowski
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: ageurts@mcw.edu.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Mailstop 8400, 13121 East 17th Avenue, Aurora, CO 80045, USA. Electronic address: Marisa.Friederich@ucdenver.edu.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Friederich
authors.affiliation: Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Mailstop 8400, 13121 East 17th Avenue, Aurora, CO 80045, USA. Electronic address: johan.vanhove@childrenscolorado.org.
authors.forename: Johan L K
authors.initials: JLK
authors.lastname: Van Hove
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: mlawlor@mcw.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Human Molecular Genetics Center and Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: ddimmock@mcw.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Dimmock
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport / Q000235:genetics; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017237:Mitochondrial Encephalomyopathies / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D039141:Muscular Dystrophy, Oculopharyngeal; D009886:Ophthalmoplegia / Q000151:congenital; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats
chemical_list: D004272:DNA, Mitochondrial; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase
keywords: DGUOK; EPR; ESR; Oxidative; Pathology; Redox; Stress; mtDNA depletion