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Müller-Höcker, J.* ; Schäfer, S.G.* ; Krebs, S.* ; Blum, H.* ; Zsurka, G.* ; Kunz, W.S.* ; Prokisch, H. ; Seibel, P.* ; Jung, A.*

Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.

Am. J. Pathol. 184, 2922-2935 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Substantia-nigra Neurons; Respiratory-chain; Common Deletion; Complex-i; Point Mutations; Stem-cell; Clonal Expansion; Renal Oncocytoma; Individual Cells; Mtdna Mutations
ISSN (print) / ISBN 0002-9440
e-ISSN 1525-2191
Journal American Journal of Pathology, The
Quellenangaben Volume: 184, Issue: 11, Pages: 2922-2935 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)