Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Abstract

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P ‫؍‬ 0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.oncocytic tumors ͉ heteroplasmy ͉ homoplasmy ͉ damaging mutation ͉ microenvironment

Lack of complex I is associated with oncocytic thyroid tumours

“…Mutations of mtDNA had previously been identified in oncocytic thyroid tumours; 26.7% of specimens showed disruptive mutations. Additional 26.7% had potentially deleterious missense mutations in one of the seven mitochondrial genes coding for subunits of complex I (Gasparre et al, 2007). Similar results were obtained in our samples, where 33% had frameshift mutations, 6% stop mutations and 17% potentially pathogenic point mutations.…”

“…Gasparre et al (2007) were, therefore, not able to report biochemical results of their specimens. It is known from cell culture studies (Hofhaus and Attardi, 1993) and from patients with complex I defects (Ugalde et al, 2004a) that severe mutations in different subunits of complex I result in reduced stability or incomplete assembly of the enzyme complex.…”

“…A study on 45 oncocytic thyroid tumours identified potentially pathogenic mutations in subunits of complex I (NADH-ubiquinone oxidoreductase) in 53% of the investigated samples (Gasparre et al, 2007). However, the effects of the observed mutations on complex I enzyme activity and protein content have not been shown particularly for the remaining cases in which clear evidence for complex I deficiency could not be shown.…”

Mitochondrial Dysfunction Impairs Tumor Suppressor p53 Expression/Function

“…Mutations in both mtDNA and nuclear genes encoding OxPhos complexes are associated with almost all types of cancers (1,3). Somatic mutations in complex I subunit-encoding genes are frequently associated with oncocytomas (5,6). A recent study with head and neck cancers suggests that there are no mutational hot spots in the mtDNA (7).…”

Quantitative Analysis of Energy Metabolic Pathways in MCF-7 Breast Cancer Cells by Selected Reaction Monitoring Assay

“…Until recently, the metabolic transformation of cancer cells was studied primarily at the level of genome (6), transcriptome (7), and metabolome (8). These studies discovered new mutations (9, 10), cancer-related alternative splicing isoforms (11), and altered enzyme activities in human cancers (2).…”