title: Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.
abstract: Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P < 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P < 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.
authors.affiliation: Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.affiliation: Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Gene Center of the Ludwig-Maximilians-Universität München, Campus Großhadern, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Gene Center of the Ludwig-Maximilians-Universität München, Campus Großhadern, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Division of Neurochemistry, Department of Epileptology and Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: Division of Neurochemistry, Department of Epileptology and Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Institute of Human Genetics, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Molekulare Zellbiologie, Biotechnological Biomedical Center, Universität Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Seibel
authors.affiliation: Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany. Electronic address: andreas.jung@lmu.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016922:Cellular Senescence / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D024862:Oxyphil Cells / Q000378:metabolism / Q000473:pathology*; D010279:Parathyroid Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology*
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV