Endocrine Abstracts

JOINT711

Succinate dehydrogenase (SDH) is an enzyme complex at the centre of aerobic respiration with a dual role in the Krebs cycle and electron transport chain. Mutations in any of the four SDH subunits (SDHA, SDHB, SDHC and SDHD) have been implicated in driving tumorigenesis of neuroendocrine tumours including phaeochromocytoma and paraganglioma, underscoring the link between metabolic dysregulation and tumorigenesis. Pituitary neuroendocrine tumours (PitNETs) associated with germline or somatic SDHx mutations, particularly in the SDHB subunit, can display clinically aggressive behaviour. The molecular pathogenesis, clinical behaviour and treatment outcomes of SDHx-mutated PitNETs remain poorly characterised. The role of SDHx mutations in driving tumour development, whether alone or in concert with other factors, and the cell-of-origin of these tumours are also unknown. Understanding these pathways is essential for developing targeted therapies for these tumours. Using in vivo mouse models, we assessed the consequence of mutating Sdhb during anterior pituitary (AP) embryonic development and in postnatal stages. We utilised two Cre drivers to delete Sdhb across Rathke’s pouch in the embryo (Hesx1^Cre/+; Sdhb^fl/fl), as well as in the postnatal SOX2+ stem cell compartment (Sox2^CreERT2/+; Sdhb^fl/fl) using a tamoxifen-inducible model. We confirm a reduction in Sdhb expression and activation of pseudohypoxic signalling in the AP, with upregulation of Hif1a and its transcriptional targets, a pattern seen in other SDHx-mutated tumours. Through metabolic flux analyses, we observe metabolic reprogramming in pituitary stem cells, consistent with the Warburg effect (a metabolic switch that is a hallmark of cancer), in response to SDHB loss. Despite these changes, homozygous loss of Sdhb in our mouse models is not sufficient to lead to pituitary tumour formation. However, strikingly, loss of SDHB leads to pituitary hypoplasia, characterised by a reduction in AP volume, with normal anterior pituitary lineage commitment and differentiation. Together, these findings support a potential two-hit tumorigenesis model. They also emphasise the potential role of altered cellular metabolism in hypopituitarism, which could inform regenerative medicine approaches in the future. These have important implications for the screening, diagnosis, and treatment of SDHx-mutated pituitary disorders.