Oxidative phosphorylation patterns in pituitary adenoma/neuroendocrine tumors

PURPOSE: Pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas, exhibit marked lineage-specific heterogeneity. The underlying molecular biology of certain tumor/adenoma types, particularly gonadotroph tumors/adenomas (SF1-lineage) — which typically exhibit stable genomes — remains poorly understood. This study aimed to define expression patterns of oxidative phosphorylation (OXPHOS) system subunits across PitNET/adenoma lineages. METHODS: Immunohistochemistry was performed in 43 previously molecularly and histologically classified PitNETs/adenomas on tumor and normal adenohypophyseal tissue for VDAC1 (porin) to assess mitochondrial density and the expression of OXPHOS-subunits. Quantified staining intensity scores were used for statistical analyses, and mtDNA sequencing was successful in 21 tumors/adenomas. RESULTS: Mitochondrial density was significantly increased in PitNETs/adenomas compared with normal tissue. Alterations in OXPHOS subunits expression were non-uniform: complex I deficiency was the most frequent abnormality, often associated with disruptive mtDNA mutations, particularly in genomically stable gonadotroph tumors/adenomas. Two corticotroph tumors/adenomas with near-haploid genomes also harboured disruptive complex I mutations. Alterations in other complexes were less common and typically occurred in combination. Staining heterogeneity was frequent (24/43 tumors/adenomas), including focal expression loss, especially in SF1-lineage and all mtDNA-mutated tumors/adenomas, but also present in tumors/adenomas without mtDNA mutations. CONCLUSIONS: PitNETs/adenomas display lineage-specific and highly heterogeneous OXPHOS-system phenotypes. Complex I deficiency and mtDNA mutations occur not only in genomically stable gonadotroph tumors/adenomas but also in highly disrupted corticotroph tumors/adenomas with a near-haploid genome. Further studies including sequencing of nuclear-encoded OXPHOS-related genes are required to clarify the contribution of altered OXPHOS-subunit expression to PitNET/adenoma biology and potential clinical applications.