机构：[1]Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China研究所北京市神经外科研究所首都医科大学附属天坛医院[2]Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China首都医科大学附属天坛医院[3]Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA[4]Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA[5]Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China[6]CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, PR China[7]Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, PR China[8]Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA[9]University of Chinese Academy of Sciences, Beijing, PR China[10]Beijing Institute for Brain Disorders Brain Tumor Center, Capital Medical University, Beijing, PR China[11]China National Clinical Research Centre for Neurological Diseases, Beijing, PR China
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 14-3-3 eta was exclusively overexpressed in oncocytomas, and that 14-3-3 eta was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3 eta inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3 eta 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. (C) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
基金：
Research Special Fund
for Public Welfare Industry of Health (201402008) and
the National High Technology Research and Development
Programme of China (2014AA020610). JF
is supported by Beijing Municipal Administration of
Hospitals ‘Youth’ Programme (QML20160506) and
the National Natural Science Foundation of China
(81702455). GX is supported by the National Natural
Science Foundation of China (81472374 and
21435006). QZ, QS, CM, HW, MJS, GD, MRG, DMP
and ZZ are supported by the Intramural Research Program
of the National Institute of Neurological Disorder
and Stroke and National Cancer Institute at the National
Institutes of Health.
第一作者机构：[1]Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China[2]Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China
共同第一作者：
通讯作者：
通讯机构：[1]Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China[2]Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China[3]Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA[4]Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA[10]Beijing Institute for Brain Disorders Brain Tumor Center, Capital Medical University, Beijing, PR China[11]China National Clinical Research Centre for Neurological Diseases, Beijing, PR China[*1]Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China[*2]Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
推荐引用方式(GB/T 7714)：
Jie Feng,Qi Zhang,Chuzhong Li,et al.Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3 eta in oncocytomas[J].JOURNAL OF PATHOLOGY.2018,245(3):361-372.doi:10.1002/path.5090.
APA：
Jie Feng,Qi Zhang,Chuzhong Li,Yang Zhou,Sida Zhao...&Yazhuo Zhang.(2018).Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3 eta in oncocytomas.JOURNAL OF PATHOLOGY,245,(3)
MLA：
Jie Feng,et al."Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3 eta in oncocytomas".JOURNAL OF PATHOLOGY 245..3(2018):361-372
医学