Alterations of Oxidative Phosphorylation Complexes in Papillary Thyroid Carcinoma

Abstract

The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, with disruptive mutations in mitochondrial complex I subunits reported at very low frequency. Furthermore, metabolic diversity of PTC has been postulated owing to variable messenger RNA (mRNA) expression of genes encoding subunits of the oxidative phosphorylation (OXHPOS) complexes. The aim of the present study was to evaluate the metabolic diversity of the OXPHOS system at the protein level by using immunohistochemical staining. Analysis of 18 human PTCs revealed elevated mitochondrial biogenesis but significantly lower levels of OXPHOS complex I in the tumor tissue (p < 0.0001) compared to the adjacent normal tissue. In contrast, OXPHOS complexes II–V were increased in the majority of PTCs. In three PTCs, we found pathologic mutations within mitochondrially encoded complex I subunits. Our data indicate that PTCs are characterized by an oncocytic metabolic signature that is in low complex I is combined with elevated mitochondrial mass and high complex II–V levels, which might be an important factor for tumor formation.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome

“…Indeed, in a parallel fashion to neuromuscular diseases [ 68 ], even heteroplasmic low-penetrance mutations mapping on mitochondrial translation genes such as tRNAs and rRNAs may display deleterious consequences in tissues with high energy requirements and mitochondrial turnover [ 69 , 70 ]. We also show that, for some of the somatic mtDNA mutations occurring in the oncocytic neoplasms, their pathogenicity is reflected in the abundance of respiratory complexes as evaluated via validated IHC markers [ 13 , 46 , 54 , 55 , 56 ]. It is striking that an increasing gradient of positive OXPHOS staining correlates with both a decreasing number of pathogenic mtDNA mutations and more evident malignant features (including the mitotic Ki67 index), with the most indolent adenoma harboring the highest number of pathogenic mutations and the most aggressive and fatal carcinoma purifying the pathogenic germline variant.…”

“…Once the full spectrum of mutations was acquired in all tumors, we sought evidence for a pathogenic effect that the combination of variants may have on respiratory complexes. Indeed, it is widely accepted that mtDNA mutations in oncocytic tumors often lead to disassembly of one or more OXPHOS complexes, which can be highlighted by validated IHC staining for specific protein subunits, such as nuclear-encoded NDUFS4 [ 13 , 46 , 54 , 55 , 56 , 57 ] or mtDNA-encoded CIV subunit COXI to infer the pathogenic potential of tRNA and rRNA mutations, whose effects may impinge on mitochondrial protein synthesis [ 58 , 59 ]. We hence exploited these validated methods on the family tumors for which sufficient material was available.…”

Transcriptomic and Genetic Associations between Alzheimer’s Disease, Parkinson’s Disease, and Cancer

“…Reductions in cellular respiration and increases in glycolytic pathways are known to take place in thyroid tumors, particularly in poorly differentiated and fast-growing types [88]. In addition, protein levels of complex I elements were reported to be reduced in papillary thyroid carcinomas [89]. Furthermore, oncolytic cell tumors of the thyroid are characterized by the accumulation of defective mitochondrial carrying mutations in elements of the electron transport system complex I [90].…”

The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment

“…Recent research suggests that in PTC, elevated mitochondrial mass is combined with low complex I and high complex II–V levels [ 36 ]. The low level of complex I could be explained by the higher number of pathologic mutations in mtDNA, while high levels of complexes II–V may represent some kind of compensatory effect to attenuate the complex I deficiency.…”

“…The low level of complex I could be explained by the higher number of pathologic mutations in mtDNA, while high levels of complexes II–V may represent some kind of compensatory effect to attenuate the complex I deficiency. In addition, it is possible that tumour cells with reduced efficacy or the complete absence of complex I might have some survival advantage in comparison to tumour cells with normal complex I [ 36 ].…”