PMID- 31629659 OWN - NLM STAT- MEDLINE DCOM- 20200219 LR - 20200219 IS - 1097-4164 (Electronic) IS - 1097-2765 (Linking) VI - 76 IP - 6 DP - 2019 Dec 19 TI - KDM3A Senses Oxygen Availability to Regulate PGC-1alpha-Mediated Mitochondrial Biogenesis. PG - 885-895.e7 LID - S1097-2765(19)30724-5 [pii] LID - 10.1016/j.molcel.2019.09.019 [doi] AB - Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1alpha is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1alpha and demethylates monomethylated lysine (K) 224 of PGC-1alpha under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K(M) of oxygen for its activity, and enhances PGC-1alpha K224 monomethylation. This modification decreases PGC-1alpha's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1alpha K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1alpha monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Qian, Xu AU - Qian X AD - Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Electronic address: xqianmedres@njmu.edu.cn. FAU - Li, Xinjian AU - Li X AD - CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Shi, Zhumei AU - Shi Z AD - Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. FAU - Bai, Xiaoming AU - Bai X AD - Department of Pathology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China. FAU - Xia, Yan AU - Xia Y AD - Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Zheng, Yanhua AU - Zheng Y AD - Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Xu, Daqian AU - Xu D AD - Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Chen, Feng AU - Chen F AD - Department of Forensic Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China. FAU - You, Yongping AU - You Y AD - Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. FAU - Fang, Jing AU - Fang J AD - The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266061, China. FAU - Hu, Zhibin AU - Hu Z AD - Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. FAU - Zhou, Qin AU - Zhou Q AD - The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China. FAU - Lu, Zhimin AU - Lu Z AD - Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address: zhiminlu@zju.edu.cn. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191016 PL - United States TA - Mol Cell JT - Molecular cell JID - 9802571 RN - 0 (PPARGC1A protein, human) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Reactive Oxygen Species) RN - EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases) RN - EC 1.14.11.- (KDM3A protein, human) RN - S88TT14065 (Oxygen) SB - IM MH - Animals MH - Apoptosis MH - Brain Neoplasms/*enzymology/genetics/pathology MH - Cell Proliferation MH - Female MH - Gene Expression Regulation, Neoplastic MH - HEK293 Cells MH - HeLa Cells MH - Hep G2 Cells MH - Humans MH - Jumonji Domain-Containing Histone Demethylases/genetics/*metabolism MH - Methylation MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mitochondria/*enzymology/pathology MH - *Organelle Biogenesis MH - Oxygen/*metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/*metabolism MH - *Protein Processing, Post-Translational MH - Reactive Oxygen Species/metabolism MH - Signal Transduction MH - Tumor Burden MH - Tumor Hypoxia MH - Tumor Microenvironment OTO - NOTNLM OT - KDM3A OT - PGC-1alpha OT - hypoxia OT - mitochondrial biogenesis OT - monomethylation OT - oxygen sensing OT - tumorigenesis EDAT- 2019/10/21 06:00 MHDA- 2020/02/20 06:00 CRDT- 2019/10/21 06:00 PHST- 2018/07/25 00:00 [received] PHST- 2019/07/22 00:00 [revised] PHST- 2019/09/12 00:00 [accepted] PHST- 2019/10/21 06:00 [pubmed] PHST- 2020/02/20 06:00 [medline] PHST- 2019/10/21 06:00 [entrez] AID - S1097-2765(19)30724-5 [pii] AID - 10.1016/j.molcel.2019.09.019 [doi] PST - ppublish SO - Mol Cell. 2019 Dec 19;76(6):885-895.e7. doi: 10.1016/j.molcel.2019.09.019. Epub 2019 Oct 16.