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 types, particularly gonadotroph tumors (SF1-lineage) — which typically exhibit stable genomes — remains poorly understood. This study aimed to define oxidative phosphorylation (OXPHOS) system patterns across PitNET lineages. Methods Immunohistochemistry was performed in 43 previously molecularly and histologically classified PitNETs on tumor and normal adenohypophyseal tissue for VDAC1 (porin) to assess mitochondrial density and OXPHOS subunits of complexes I–V. Quantified staining intensity scores were used for statistical analyses, and mtDNA sequencing was successful in 21 tumors. Results Mitochondrial density was significantly increased in PitNETs compared with normal tissue. OXPHOS alterations were non-uniform: complex I deficiency was the most frequent abnormality, often associated with disruptive mtDNA mutations, particularly in genomically stable gonadotroph tumors. Two corticotroph tumors 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), including focal expression loss, especially in SF1-lineage and all mtDNA-mutated tumors, but also present in tumors without mtDNA mutations. Conclusions PitNETs display lineage-specific and highly heterogeneous OXPHOS phenotypes. Complex I deficiency and mtDNA mutations occur not only in genomically stable gonadotroph tumors but also in highly disrupted corticotroph tumors with a near-haploid genome. Further studies including sequencing of nuclear-encoded OXPHOS-related genes are required to clarify the contribution of OXPHOS and mitochondrial pathways to PitNET biology and potential clinical applications.