PMID- 34963686 OWN - NLM STAT- MEDLINE DCOM- 20220707 LR - 20230216 IS - 1530-0307 (Electronic) IS - 0023-6837 (Linking) VI - 102 IP - 7 DP - 2022 Jul TI - Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells. PG - 722-730 LID - 10.1038/s41374-021-00724-0 [doi] AB - Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy. CI - (c) 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology. FAU - Luo, Min AU - Luo M AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Liu, Yu-Qi AU - Liu YQ AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Zhang, Hua AU - Zhang H AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Luo, Chun-Hua AU - Luo CH AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Liu, Qing AU - Liu Q AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Wang, Wen-Ying AU - Wang WY AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - He, Zhi-Cheng AU - He ZC AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Chen, Cong AU - Chen C AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Zhang, Xiao-Ning AU - Zhang XN AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Mao, Min AU - Mao M AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Yang, Kai-Di AU - Yang KD AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Wang, Chao AU - Wang C AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Chen, Xiao-Qing AU - Chen XQ AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Fu, Wen-Juan AU - Fu WJ AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Niu, Qin AU - Niu Q AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Bian, Xiu-Wu AU - Bian XW AUID- ORCID: 0000-0003-4383-0197 AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. FAU - Shi, Yu AU - Shi Y AUID- ORCID: 0000-0001-8436-604X AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. drshiyu@126.com. FAU - Ping, Yi-Fang AU - Ping YF AD - Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. pingyifang@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211228 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - EC 2.3.1.21 (CPT1A protein, human) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) SB - IM MH - Animals MH - *Brain Neoplasms/metabolism MH - *Carnitine O-Palmitoyltransferase/genetics/metabolism MH - Cell Line, Tumor MH - *Glioblastoma/metabolism MH - *Glioma/metabolism MH - Humans MH - Mice MH - *Mitochondrial Dynamics MH - Neoplastic Stem Cells/metabolism EDAT- 2021/12/30 06:00 MHDA- 2022/07/08 06:00 CRDT- 2021/12/29 05:32 PHST- 2021/08/01 00:00 [received] PHST- 2021/12/16 00:00 [accepted] PHST- 2021/12/15 00:00 [revised] PHST- 2021/12/30 06:00 [pubmed] PHST- 2022/07/08 06:00 [medline] PHST- 2021/12/29 05:32 [entrez] AID - S0023-6837(22)00207-0 [pii] AID - 10.1038/s41374-021-00724-0 [doi] PST - ppublish SO - Lab Invest. 2022 Jul;102(7):722-730. doi: 10.1038/s41374-021-00724-0. Epub 2021 Dec 28.