RC5.6 - ECE_2859 - Mitochondrial metabolic dependencies shape anterior pituitary homeostasis and disease

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Abstract Cell metabolism is fundamental to anterior pituitary (AP) function, enabling endocrine cells to meet the energetic and biosynthetic demands of hormone production and secretion. While pituitary cell types are presumed to rely on distinct metabolic pathways to support hormone synthesis and cell fate decisions, these dependencies remain poorly defined. Notably, mutations in mitochondrial metabolic enzymes, including succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), are associated with endocrine tumours, including the pituitary, implicating metabolic dysregulation in pituitary disease. However, whether altered cellular metabolism is sufficient to drive pituitary pathology in vivo is unknown. Understanding the metabolic dependencies that govern AP homeostasis has translational relevance for regenerative strategies and targeted metabolic therapies. Using mouse models, we disrupted key oxidative metabolic enzymes, including Succinate Dehydrogenase B (SDHB) in the TCA cycle and electron transport chain (ETC), and NDUFS4 in Complex I of the ETC, to define the role of oxidative metabolism in pituitary homeostasis and disease. We used complementary Cre drivers to mutate Sdhb either during embryonic pituitary development (Hesx1Cre/+;Sdhbfl/fl) or postnatally in the SOX2⁺ stem cell compartment (Sox2CreERT2/+;Sdhbfl/fl). In both models, Sdhb loss activated pseudohypoxic signalling in the AP, with upregulation of Hif1a and downstream targets, and induced metabolic reprogramming in pituitary stem cells consistent with a Warburg-like shift. Despite these tumour-associated metabolic changes, SDHB deficiency alone was insufficient to drive pituitary tumour formation. Instead, SDHB loss resulted in marked pituitary hypoplasia with preserved lineage commitment and differentiation. Consistent with this, Ndufs4−/− mice exhibited pituitary hypoplasia with reduced AP proliferation, increased lactate dehydrogenase expression, and expansion of the SOX2⁺ stem cell compartment, without loss of endocrine cell identity. Notably, Ndufs4 deficiency also led to the formation of ectopic, fully specified pituitary tissue connecting the anterior and intermediate lobes, characterised by a patterned SOX2⁺ stem cell epithelium. Together, these findings reveal that intact oxidative metabolism is a critical constraint on AP growth and tissue architecture but is dispensable for lineage specification and endocrine identity. This unexpected dissociation between growth and differentiation highlights a remarkable capacity for metabolic adaptation in the AP and provides new insight into how mitochondrial dysfunction contributes to pituitary hypoplasia, ectopia, and tumour susceptibility, with implications for regenerative and metabolic therapeutic strategies.

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