title: Mosaic Deficiency in Mitochondrial Oxidative Metabolism Promotes Cardiac Arrhythmia during Aging.
abstract: Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency.
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, Köln 50931, Germany.
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Baris
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, Köln 50931, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ederer
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, Köln 50931, Germany.
authors.forename: Johannes F G
authors.initials: JF
authors.lastname: Neuhaus
authors.affiliation: Department of Pediatrics, University Hospital of Köln, Köln 50924, Germany.
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.affiliation: Max Planck Institute for Metabolism Research, Köln 50931, Germany; Center for Molecular Medicine Cologne (CMMC), University of Köln, Köln 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Köln 50674, Germany.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.affiliation: Max Planck Institute for Metabolism Research, Köln 50931, Germany; Center for Molecular Medicine Cologne (CMMC), University of Köln, Köln 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Köln 50674, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Pal
authors.affiliation: Max Planck Institute for Metabolism Research, Köln 50931, Germany; Center for Molecular Medicine Cologne (CMMC), University of Köln, Köln 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Köln 50674, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Department of Epileptology and Life and Brain Center, University of Bonn, Bonn 53105, Germany.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Peeva
authors.affiliation: Department of Epileptology and Life and Brain Center, University of Bonn, Bonn 53105, Germany.
authors.forename: Gabor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: Department of Epileptology and Life and Brain Center, University of Bonn, Bonn 53105, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Department of Radiology, University Hospital of Köln, Köln 50931, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Hickethier
authors.affiliation: Department of Radiology, University Hospital of Köln, Köln 50931, Germany.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Bunck
authors.affiliation: University Hospital of Bonn, Department of Medicine II-Cardiology, Bonn 53105, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Stöckigt
authors.affiliation: University Hospital of Bonn, Department of Medicine II-Cardiology, Bonn 53105, Germany.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Schrickel
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, Köln 50931, Germany; Center for Molecular Medicine Cologne (CMMC), University of Köln, Köln 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Köln 50674, Germany. Electronic address: rudolf.wiesner@uni-koeln.de.
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D000375:Aging; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D010100:Oxygen