Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14‐3‐3η in oncocytomas

Abstract

Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3η was exclusively overexpressed in oncocytomas, and that 14-3-3η was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3η inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3η overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Metabolic profiling reveals distinct metabolic alterations in different subtypes of pituitary adenomas and confers therapeutic targets

“…In general, PRL-PA, GH-PA, and GH-PRL-PA showed increased levels of glutamine and α-KG, suggesting powerful anaplerosis of glutamine. Alanine and pyruvate were increased, suggesting that pyruvate was repurposed to alanine synthesis from ATP production, as has previously been found in oncocytoma [10]. Citruline and ornithine were also found to be increased in these pituitary adenomas.…”

“…Pituitary adenoma cells are suggested to undergo significant metabolic reprogramming due to their aberrant hormone production, and these metabolic alterations, in turn, may influence the progression of the tumor [9]. For instance, we previously demonstrated that pituitary oncocytoma, a specific subtype of pituitary adenoma with significant mitochondrial hyperplasia, reprogrammed its metabolism by suppressing glycolysis to facilitate mitochondrial biogenesis [10]. However, the metabolic characteristics of other subtypes of pituitary adenomas are largely unknown.…”

Metabolomics—A Promising Approach to Pituitary Adenomas

“…Two articles were excluded because they provided proteomics data (57, 58) and another article was excluded, evaluating compounds with a molecular weight greater than 1,500 Da (59). A study that evaluated other types of pituitary tumors (60) and a review (61) were also excluded. Finally, 18 studies enrolling 241 patients with PA were eligible for our review (Table 1).…”

Mitochondrial Dysfunction Pathway Networks and Mitochondrial Dynamics in the Pathogenesis of Pituitary Adenomas

“…The study on SDH subunit B (SDHB) (+/–) mice finds that SDHx-deficiency is a main initiator to result in the cascade of molecular events for the formation of pituitary adenomas (46). The whole-exome sequencing analysis of pituitary oncocytomas found mitochondrial DNA mutations, respiratory complex I dysfunction, and reductions of lactate and lactate dehydrogenase A (LDHA) (48). Besides glycometabolism change, lipid metabolism is also alerted in pituitary adenomas.…”