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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. Free Radic Biol Med 2016 Mar;92:141-151

Date

01/17/2016

Pubmed ID

26773591

Pubmed Central ID

PMC5047058

DOI

10.1016/j.freeradbiomed.2016.01.001

Scopus ID

2-s2.0-84957568061 (requires institutional sign-in at Scopus site)   15 Citations

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.

Author List

Bennett B, Helbling D, Meng H, Jarzembowski J, Geurts AM, Friederich MW, Van Hove JLK, Lawlor MW, Dimmock DP

Authors

Brian Bennett D.Phil. Professor and Chair in the Physics department at Marquette University
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
DNA, Mitochondrial
Disease Models, Animal
Electron Spin Resonance Spectroscopy
Electron Transport
Humans
Intestinal Pseudo-Obstruction
Mitochondria
Mitochondrial Diseases
Mitochondrial Encephalomyopathies
Muscular Dystrophy, Oculopharyngeal
Ophthalmoplegia
Oxidation-Reduction
Oxidative Stress
Phosphotransferases (Alcohol Group Acceptor)
Rats