Contents lists available at ScienceDirect Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig S6 kinase 1 plays a key role in mitochondrial morphology and cellular energy flow Quangdon Tran a , Jae-Hun Jung b , Jisoo Park a , Hyunji Lee a , Youngeun Hong a , Hyeonjeong Cho a , Minhee Kim a , Sungjin Park a , So-Hee Kwon d , Seon-Hwan Kim e , George Thomas f , Kwang Pyo Kim b,c, ⁎ , Myung-Haing Cho g, ⁎⁎ , Jongsun Park a, ⁎⁎ a Department of Pharmacology and Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea b Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea c Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea d College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, South Korea e Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea f Laboratory of Metabolism and Cancer, Catalan Institute of Oncology, ICO, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain g Laboratory of Toxicology, College of Veterinary Medicine Seoul National University, Seoul 08826, South Korea ARTICLE INFO Keywords: S6K1 Drp1 Fission Metabolic shift Mitophagy OxPhos ABSTRACT Mitochondrial morphology, which is associated with changes in metabolism, cell cycle, cell development and cell death, is tightly regulated by the balance between fusion and fission. In this study, we found that S6 kinase 1 (S6K1) contributes to mitochondrial dynamics, homeostasis and function. Mouse embryo fibroblasts lacking S6K1 (S6K1-KO MEFs) exhibited more fragmented mitochondria and a higher level of Dynamin related protein 1 (Drp1) and active Drp1 (pS616) in both whole cell extracts and mitochondrial fraction. In addition, there was no evidence for autophagy and mitophagy induction in S6K1 depleted cells. Glycolysis and mitochondrial re- spiratory activity was higher in S6K1-KO MEFs, whereas OxPhos ATP production was not altered. However, inhibition of Drp1 by Mdivi1 (Drp1 inhibitor) resulted in higher OxPhos ATP production and lower mi- tochondrial membrane potential. Taken together the depletion of S6K1 increased Drp1-mediated fission, leading to the enhancement of glycolysis. The fission form of mitochondria resulted in lower yield for OxPhos ATP production as well as in higher mitochondrial membrane potential. Thus, these results have suggested a potential role of S6K1 in energy metabolism by modulating mitochondrial respiratory capacity and mitochondrial mor- phology. 1. Introduction Mitochondria are critical cellular organelles, best known for their role in providing efficient energy support through the chemiosmotic process of oxidative phosphorylation (OxPhos). In the 1960s, their role in aerobic energy transduction through the characteristic chemiosmotic mechanism of OxPhos first began to be clarified [1,2]. Since then, mi- tochondria have also been shown to perform a variety of roles in pro- cesses such as the transduction of metabolic and stress signals [2–5], the production of free radicals such as reactive oxygen species (ROS) [4,6], and the induction of programmed cell death [2,5,7]. The accu- mulation of damaged mitochondria can be unfavorable to cells. Mitochondrial quality and quantity are therefore strictly monitored to ensure balanced cell physiology. Damaged or unwanted mitochondria can be selectively removed by mitochondrial autophagy or mitophagy, a catabolic process for lysosome-dependent degradation. The molecular mechanism of mitophagy has begun to emerge. Several mitophagy re- ceptors have been reported, including: ATG32 in yeast [8,9], NIX/ BNIP3L [10], BNIP3 [11], fun14 domain-containing protein 1 (FUNDC1) in mammalian cells [12] interacting with LC3 via their conserved LC3 interaction region for mitophagy. E3 ubiquitin ligase Parkin and phosphatase and tensin homolog (PTEN)-induced putative protein kinase 1 (PINK1) also have critical functions for the removal of depolarized mitochondria [13,14]. https://doi.org/10.1016/j.cellsig.2018.04.002 Received 16 January 2018; Received in revised form 5 April 2018; Accepted 13 April 2018 ⁎ Correspondence to: Kwang Pyo Kim, Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, 17104 ⁎⁎ Corresponding authors. E-mail addresses: kimkp@khu.ac.kr (K.P. Kim), mchotox@snu.ac.kr (M.-H. Cho), insulin@cnu.ac.kr (J. Park). Cellular Signalling 48 (2018) 13–24 Available online 17 April 2018 0898-6568/ © 2018 Published by Elsevier Inc. T