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Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14‐3‐3η in oncocytomas
Author(s) -
Feng Jie,
Zhang Qi,
Li Chuzhong,
Zhou Yang,
Zhao Sida,
Hong Lichuan,
Song Qi,
Yu Shenyuan,
Hu Chunxiu,
Wang Herui,
Mao Chengyuan,
Shepard Matthew J,
Hao Shuyu,
Dominah Gifty,
Sun Mitchell,
Wan Hong,
Park Deric M,
Gilbert Mark R,
Xu Guowang,
Zhuang Zhengping,
Zhang Yazhuo
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5090
Subject(s) - mitochondrial biogenesis , biology , mitochondrion , glycolysis , lactate dehydrogenase a , microbiology and biotechnology , oxidative phosphorylation , respiratory chain , stable isotope labeling by amino acids in cell culture , mitochondrial respiratory chain , biogenesis , biochemistry , metabolism , proteomics , gene
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.