Journal Article

Regionalized Pathology Correlates with Augmentation of mtDNA Copy Numbers in a Patient with Myoclonic Epilepsy with Ragged-Red Fibers (MERRF-Syndrome)

von Moers, Arpad, Brinckmann, Anja, Wilbert, Friederike, Stoltenburg-Didinger, Gisela, Zwirner, Angelika, Weiss, Claudia, Schuelke, Markus, Wilichowski, Ekkehard

2010

Overview

Human patients with myoclonic epilepsy with ragged-red fibers (MERRF) suffer from regionalized pathology caused by a mutation in the mitochondrial DNA (m.8344A→G). In MERRF-syndrome brain and skeletal muscles are predominantly affected, despite mtDNA being present in any tissue. In the past such tissue-specificity could not be explained by varying mtDNA mutation loads. In search for a region-specific pathology in human individuals we determined the mtDNA/nDNA ratios along with the mutation loads in 43 different post mortem tissue samples of a 16-year-old female MERRF patient and in four previously healthy victims of motor vehicle accidents. In brain and muscle we further determined the quantity of mitochondrial proteins (COX subunits II and IV), transcription factors (NRF1 and TFAM), and VDAC1 (Porin) as a marker for the mitochondrial mass. In the patient the mutation loads varied merely between 89-100%. However, mtDNA copy numbers were increased 3-7 fold in predominantly affected brain areas (e.g. hippocampus, cortex and putamen) and in skeletal muscle. Similar increases were absent in unaffected tissues (e.g. heart, lung, kidney, liver, and gastrointestinal organs). Such mtDNA copy number increase was not paralleled by an augmentation of mitochondrial mass in some investigated tissues, predominantly in the most affected tissue regions of the brain. We thus conclude that \"futile\" stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF-syndrome.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accidents / Adolescent / Apoptosis / Augmentation / Base Sequence / Blotting, Western / Brain / Copy number / Deoxyribonucleic acid / DNA / DNA Primers / DNA, Mitochondrial - genetics / Epilepsy / Female / Genetic testing / Genetics and Genomics/Gene Expression / Genetics and Genomics/Gene Function / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Medical Genetics / Genomes / Humans / Kidneys / Liver / Load / Loads (forces) / Lungs / Male / Medical research / Medical schools / MERRF Syndrome / MERRF Syndrome - genetics / MERRF Syndrome - pathology / Mitochondria / Mitochondrial DNA / Motor vehicles / Muscles / Musculoskeletal system / Mutation / Myoclonic epilepsy / Organs / Oxidative stress / Pathology / Patients / Pedigree / Permeability / Polymerase Chain Reaction / Proteins / Putamen / Skeletal muscle / Statistics / Studies / Tissues / Traffic accidents / Transcription factors